Gupta1983 Hallucinogen QSAR Review

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Chem. Rev. lQ83 ,8 3 , 633-649

QSAR Studies on Hallucinogens

833

SATYA P.GUPTA,” PRITHVI SINGH, and MAHESH C. BINDAL

Biria Institute of Technoiogy and Science, Piiani-333031, India

Received March 23, 1982 (Revised Manuscript Received November 23, 1982)

Confen s

I. Introduction 633

11. Basic Postulates Concerning Mode of Action of 63 4Hallucinogens

111. Recent Developm ents

IV. Results of QSAR Studies

A. Phenylalkylamines

1. Hallucinogenic Activity

2. Rabbit Hyperthermia and LSD-like

Effects in Animals

3. Activity with Serotonin Receptors

B. Indoleaikylamines

C. Lysergic Acid Derivatives

V. Discussion

V I . Conclusions

V I . References

63 4

63 5

63 5

63 5

63 7

639

63 9

64 2

64 4

647

647

I . Infroducflon

Hallucinogens commonly refer to the drugs that acta t central nervous system (CNS) to produ ce changes inthought, perception, and mood, sense of time and p lace,memory, and accustomed patterns of outer and inneruniverse of “n orm al” individuals. Such dru gs have also

been called psychedelic (m ind manifesting)l a gents toexpress the general activation of psychic phen ome nawithout conn otation of negative or morbid components.Another term commonly used for these CNS agents is“psychotomimetic” which implies disturbances ofmemory, h yperexcitability, deep depressive w ithdrawal,or even violent behavior resem bling psychoses.2 How-ever, since the extraordinary, unexpected, colorful,world-encompassing, or frightening visions co njured u pby these agents are comparable to autogeneous hallu-cinations, the te rm “hallucinogen” appea rs to be m ostapprop riate for them.

Although the g eneral medical consensus is tha t thereis little poten tial for m edical utility in hallucinogens,

some psychiatrists consider that they are a valuableadjunct to psych otherap y in carefully selected patientswho possess neuroses and display obsessive or com-pulsive manifestations or have othe r disorders th at arethought to be of a similar typ e (e.g., alcoholism, sexua ldev ia tion, a ~ t i s m ) . ~he intention is to use the effectsof hallucinogens to overcome inhibitions and rep res-sions, and release the thoug hts a nd m emories that havebeen repressed from consciousness. Hofm ann4 de-scribed the psychotherapeutic values of these psy-chomimetic drugs in the following terms:(1)They are able to release the p atien t from his austic

fixation and isolation by shattering and transforminghis customary etting. As a result the patie nt can obtain

0009-2665/83/0783-0633$08.50/0

a m ore satisfactory relationship with the therapist .(2) Following the general psych ic activatio n elicited

by these d r u g s , the resistance of t he ego disappears, andforgotten and repressed memories may be evoked.Even experiences of early childhood are often remem -bered. Th is is of major importance for the success ofpsychotherapy, particularly when the experiences cor-nered are those which have led to psychic trauma.

One of the earliest bases for the research inte res t inhallucinogens was, however, the assum ption th at th edrug-induced hallucinatory stat e provided a m odel forschizophrenia and t ha t the mo del psychosis producedby these drugs might be used to a certain extent as an

aid in psychotherapy.s Tho ugh this assumption nevergained favor in experimental psychiatric circles, the“altered state of consciousness” th at results from theapplication of these drugs has, besides a purely he-donistic value, a pote ntial for enhanc ing creativity andself-analysis! These two properties, th e one as prosaicas the oth er is audacious, would seem to guaran tee acontinuing fascination with these drugs in th e researchcommunity.

Presently several compounds are known which causepsy~hoses.~ owever, the true hallucinogens, which

1

l a , Y = CH,CH,NH,; R = Hl b , Y = CH,CH(CH,)NH,; R = HIC,Y = CHOHCH,NH,; R = 3 ,4 - (OH) ,I d , Y = CH,CH,NH,; R = 3 ,4 - (OH) ,

H

2

2b, R,, ,= H ; R = 5 - O H2a , R , R , , R , = H

3

3a , R , , R, = C,H,; R,, R, = H3b, R , , R, = C,H,; R, = H ; R, = Br

3 d , R , = H, R, = CH(C,H,)CH,OH; R, = CH,; R, = H3c , R,, ,,R,,R,= H

0 1983 American Chemical Society



634 Chemical Revlews. 1983. Vol. 83. o. 6 Gupta. Singh. and'Bindal

have been used deliberately to produce psychosis andwhich have been extensively studied, belong to thefollowing chemical classes: (a) phenylalkylamines ( I ) ,(b) indolealkylamines (2). and (c) lysergic acid deriva-tives (3).

I I . Basic Postulates Concerning Mode of Action

of Hallucinogens

Since the presumed brain neurohumors nor-epinephrine (IC) and serotonin (5-hydroxytryptamine,S H T , 2b) are structurally similar to phenylethylamine(la)and tryptamine (Za), espectively, it was thoughtth at hallucinogens might effect synaptic transmissionin the brain. One theory postulated th at hallucinogensmight act in the brain asantim etabo lites of serotonin,Rgand was based on th e finding tha t LSD (lysergic aciddiethylamide) in low concentration antagonized thecontractile effect of serotonin on smooth muscle.'nHowever, 2-Br-LSD (3b), which has 50% more antis-erotonin activity tha n LS D on isolated rat u terus andwhich readily enters th e brain, has no hallucinogenicactivity." Mescaline (3,4,5-trimethoxyphenylethyl-amin e), an effective hallucinogen, is devoid of antiser-otonin activity on rat u te ru ~ . ' ~ owever, when attem ptswere made to r elate the electronic structur e of hallu-cinogens with their activity, it was pointed out thatthese drugs exert their biological effects through th eformation of charge-transfer complexes with th e re-c e p t o r ~ . ' ~ - ~ ~owever, as the study progressed, muchconfusion arose regarding this idea.

I I I . Recent Developments

As the inte rest was aroused in the mech anism of ac-tion of hallucinogens, people started making studies ontheir structure-activity relationships. Th e results of

such studies were mostly expressed in terms of thecorrelations of the potency of action with chemicalstructure, functional group identity and physics, ki-netics of body dynamics, organ and tissue distribution,agonist or antagonist efficacy in competition with otherdrugs or normal biochemicals, and for tha t m atter, anyphenomenon that can be measured or computed. Ifhallucinogenic phenylalkylamines, indolealkylamines,and lysergic acid derivatives form a c lass, it is naturalto ask w hat is the common structural feature amongthem an d how is it related with the activity. Th is lineof enquiry led Snyder and R ic h e l s ~ n '~ ~ '~o suggest tha thallucinogenic potency depend s in pa rt upon the degreeto which a molecule tends to mimic the ring structure

of LSD. An implication of this theory was th a t lysergicacid derivatives, indolealkylamines, and phenylalkyl-amines act upon the same central receptors. Recentlystrong arguments have been made to supp ort a sero-tonin receptor as a site of action.

After Wooley and Sha@ made the suggestion thathallucinogens might a ct asantimetabolites of serotonin,various authors exam ined the ability of tryptamines andrelated com ponents to interact as agonists or antago-nists with seroton in receptor s of various isolated tissuepreparations.*% Using a somewhat differen t approachGlennon and co-workers25-2Rnvestigated the bindingaffinities of N,N-dialkyltryptamines and related ana-logues for the seroton in receptors of isolated ra t stom -

Bornh 1945. Satya P. Gupta received hisM.Sc.wee in physicalChmbtry from the ullverslty of Allahabad in 1967. After obtain-his 0.Phil. degree in 1971 from the Same university for his workon molecular orbital (MO) meories with Rof . Balkrishna. he movedto Tata Instituteof Fundamental Research (TIFR). Bombay. wherehe associated himself wnh the group of Or. G. Govil and worked

on he use of MO M s o study the w n f ~ b sf biobgicallympatanl md ec uk such as phosphoiipkls. He pined Btla Instituteof Technology and Science (BITS). Piiani. In 1973 as an AssistantProfessor of Chemistry. He continues there as an AssociateRofessor and isworking on heofeticai aspects of&q esign. Heis also interested in the use of MO theories to study other bio-chemical and biophysical phenomena of interest.

mvl

Sir@ wasban

h 1951. He &ed his M.Sc. (Chemistry)in 1974 and his Ph.0. in 1978 from BITS, Pilani. For his Ph.0.heworked with Or . Gupta and after spending anomet year with himas a postdoctoral fellow he oined the faculty of BITS. His maininterests lie inttm study of the cmelatbn of electronic structuresof drugs with their biological activity.

_ .!

Mahesh C. Bindal was born in 1948. He recelvedhis M.Pharm.in 1972 from PunJab University. Chandigarh. After receiving hisM.Pharm. ha served in a few medical colleges until he was ap-pointedas an Appraising Officer. Drugs and Pharmaceuticals. in1976. He left this post after a few month to pursue his academicinterests. and pined the stafl at BITS. Pihni. where he remaineduntil the end of 1981. br ing this periodhe worked withh.Guptaand obtained his Ph.0. degree. He then joined L.L.R.M. Medical

Collage. Meerut. as a Reader in Pharmacy. and from there hereentered the administrative world to occupythe chau of Drugs andFood Controller of Uttar Pradesh.



QSAR Studies on Hallucinogens Chemical Reviews, 1983,Vol. 83,No. 6 635

ach fundus preparation. Aghajanian and Ha ig le P em-ploying a microinotophoretic techniqu e have demon -strated that low doses of hallucinogenic tryptam ines actpreferentially upon presyn aptic serotonin receptors toinhib it raphen eurons . Be nn ett and Snyder30t31haveinvestigated the binding of tryptam ines to calf brainmemb rane preparations and have suggested tha t thebinding sites involved migh t be postsynaptic serotoninreceptors . Similarly phen ylalkylam ines have been

found to have direct actions on serotonin receptors,both as agonist^^^-^^ an d a s a n t a g ~ n i s t s . ~ ~lennon eta l . 2 6 1 3 7 1 3 8 measured their binding affinity with these re-ceptors of ra t fundus preparation an d found that certainphenyl-substi tuted derivatives possess an affinitygreater tha n tha t of some indolealkylamines. Th echemical similarities between the indolic hallucinogensand serotonin were apparent, but some successfulstud ies of cross-tolerance (vide reviews by Brawley a ndD ~ f f i e l d ~ ~nd by B r i m b l e~ om be~ )ad suggested tha tchemically unrelated drugs might also act there.Smythies et al.& catagorically suggested that mescaline,N,N-dimethyltryptamine, and LS D all act on serotoninreceptors.

Thu s, al though the serotonin hypothesis appears tobe a ttractive, the mechanism of hallucinations at re-cep tor level is still not clear. T he hallucinogenic po-tency of phenylalkylamines, a widely studied class ofhallucinogens, has b een foun d to have no direct corre-lation with their binding a ffinity for serotonin receptors.Man y review articles on this s ubject have been w rit-ten16,739741-48ut none of them have been able to presentany unified theory.

At molecular level some molecular orbital parame ters,such as energy of th e highest occupied molecular orbital(EHOM0),13-15nd c ertain physicochem ical prope rties,s uc h as u ltr av io le t a b s ~ r p t i o n , ~ ~tability of charge-t ransfer complexes,5o and na tive f l u o re s~ en ce ,~ ~llsuggestive of charge -transfer processes were foun d tohave significant correlations with hallucinogenic po-tencies. Th is simply suggested tha t electronic factorsare relevan t to the mechanism of pharm acological ac-tions of hallucinogenic com poun ds. However, thissuggestion could also not be generalized, as such cor-relation studies h ad been m ostly m ade on only one classof hallucinogens, i.e., phenylalkylamines.

In order to provide an aid to the understanding ofmechanism of actions of this class of drugs, someworkers became interested in the quantiative struc-ture-activity relationships (QSA R) stud ies on thesedrugs. In the recen t past, therefore, several QSARstudies were carried out. Th e aim of th e present articleis to compile all such studies a nd exam ine critically howfar these studies have been able to help understand themechanism of actions of hallucinogens.

I V . Results of W A R Studles

QSAR studies could be star ted in the real sense onlywhen Shulgin e t al .52 compiled the human da ta ofhallucinogenic activity for a fairly large number ofphenylalkylamines. Since the n many investigatorsbecame interested in QSAR studies, and when th e da tabeca me available on any kind of activity of hallucino-gens of any class, attem pts were m ade to correlate them ,by regression analysis, with various physical, physico-

cemical, and e lectronic parameters. This section of thearticle will present t he resu lts of all such QSAR studiesma de until now. A few co rrelation equations involvingonly a topological parameter-the molecular connec-tivity index, have been recently discussed by Kier a ndG l e n n ~ n . ~ ~

A. Phenylalkylamines

Phenylalkylamines are t he most widely studied classof hallucinogens. Th ey have been stu died for a varietyof actions, such ashallucinogenic activity indirect interaction with serotonin receptors (vide section111), and hypertherm ic potency in rabbits.- Atte mp tswere made to correlate the se activities with electronic,topological, or ph ysicochemical prope rties of th e mol-ecules. Resu lts tha t were obtained are as follows.

1. Hallucinogenic Activity

Some of the human data (Table I) compiled byShulgin et al.52was first correlated by Kang and Gr ee d5with th e energy of highest occupied molecular orbital

(EHOMO)btained by INDO (interm ediate neglect ofd if fe ren tia l over lap) ap p ro ~ i m a t i o n~ ~s

log MU = 19.07 + 3 5 . 6 5 E ~ o ~ o

n = 13, r = 0.753, Fl,ll= 14.36 (1)

where MU sta nd s for th e activity in mescaline units-the ratio of th e effective dose of m escaline to th at ofdrug. Among the statist ical param eters, n epresentsthe nu mber of data points, r th e c orrelation coefficient,and F the F ratio between the variances of calculatedand observed activities. W hen the doses were expressedin moles, the equation obtained was

log mMU = 18.07 + 35.10EHoMo

n = 13 , r = 0.756, F1,11 = 14.62 (2 )

Correlations expressed by both th e equations (eq 1and2) were however only mo derately significant. EHoMo isa measure of ionization potential (IP) or electron-do-nating capability of m olecule. A little better correlationwas therefore obtained when Domelsm ith and HoukGO>61used direct experimental ionization potential m easur edby photoelectron spectroscopy.62 Th ey treate d com-pounds 7-11, 14, 15, 24, 30, and 3 1 of Table I and(2,5-dimethoxy-4-(methylthio)phenyl)isopropylamine(5 3 in Table 111)with mMU = 49.1, and obtained theequation

log mMU = 19.53 - 2.37 IP

n = 11,r = 0.86 (3)

which was furthe r improved by inclusion of l-oc ta-nol-water pa rtitio n coefficient (P)n the regressionanalysis, accounting for the role of hydrophobic char-acte r also of molecules in hallucinogenic activity.

log mMU = 11.15 - 1.48 IP + 0.78 log P

n = 11,r = 0.94 (4 )

For a small series of a mp hetam ines (phenylisopropyl-amines), the d ata of Shulgin e t al. were however found

to be additionally correlated with other electronic



636 Chemical Reviews, 1983, Vol. 83, No. 6 Gupta, Singh, and Bindal

T A B L E I. Halluc inogenic Activ ity and R elated Elec tronic and P hys icochemical Parameters for Phenyla lkylamines

X

c o m p d R X MUa E H O M O , ~u e V log pd

4 3 .4 .5-(OCHm). H 1 -0 .5226 1.1856

789

10111 21 31 41 5161 71 819202 1222 3

242 52 6272 8293 031323 33 43 5363 73 8

2;4;5-(OCH; j;3 - 0CH 3-4, -( OCH ,O

4-OCH.2 , 4 - ( 0 6 H 3 ) ,

2 ,5-(OCH3 z

2,4 ,5-(OCH313

3,4,5-(OCH3)3

2,3,5-(OCH3)32,3 ,6-(OCH3 3

2,4,6-(OCH3)33,4-(OCH,O)3-OC H3-4 ,5 - (OC H,O)2-OCH3-4,5-(OCH,O)2-OC H3-3 ,4 - (OC H,O)2 ,3 - (OCH,O)-4-OCH,2 ,5 - (OC H3) , -3 ,4 - (OC H20)2 ,3 - (OCH3),-4 ,5-(OCH,O)

2 ,3 ,4 ,5 - (OC H3) ,2,5-( OCH, ),-4-OC,H

2 ,5 - (OC H3) , -4 -C H32 ,5 - (OCH3),-4-C,H52,5-(OCH 3),-4-( -C3H,)2 ,5-(OCH 3),-4-( -C,H,)2 ,5-(OCH,) ,-4-( n-C5H ll

3 ,4-(OCH3 2

2,3,4-(OCH3)33-OCH3-4,5-(OC,H,O)2-OC2H,-4 ,5-( CH,) ,2 ,4 - (OC H3) , -5 -OC ,H ,3 ,4 ,5 - (OC H, 3

4-OC H,

3,4-(OCH3z

2 - O C H 3 - 3 , 4 - ( O C H , 0 )

2 ,5 - (OCH, ),-4-Br

11

5582 .2

1 74

1 310

32. 7

1 210

31 2

56

1 5

8 01 0 080361 0

4 0 0< 1< 2< 1< 7< 7< 2<1< 0 . 2< 5

-0 .5262-0 .5194-0 .501 2-0 .5218-0 .5001-0 .5026-0 .5112-0.52 17

-0 .5126

-0 .4929

-0 .5238-0 .5274

8.167 .917.708 .167.66

7.768 . 0 1

7.62

7.948 .038 .09

1 . 4 41 . 3 8

1 . 7 71 . 7 51 . 8 81 . 4 81 . 7 41 . 6 11 . 7 31 .571 . 6 81.802 .422.041 . 7 22.162.541 . 4 82.24

2.082 .813.313 . 8 14 . 3 12 .581 . 0 01 . 3 6

Refere nce 52, for comp oun d 29 see : Shulgin , A. T. ; Sa rge n t , T . ; Naranjo, C. Pharmacology 1 9 7 1 , 5, 1 0 3 . Reference15. Reference 60. Refere nce 63.

prope rties also. Fo r compounds 7-11 and 31, Baileyand Verner49 howed log MU to be correlated with UVabsorption maximum (A ) and with molar absorptivity(e ) as exhibited by

log MU = -9.96 + 0.038h

r = 0.94, F1,4 28.15, p < 0.01 (5 )

log MU = 0.176 + 0.000213~

r = 0.94, F1,4 27.92, p < 0.01 (6)

respectively. T o supp ort the idea tha t hallucinogensexe rt their activity by the form ation of charge-transfercomplexes with the receptor, Sung and Parkerm mea-sured th e association constant ( K ) for amphetamine-1,4-dinitrobenzene complexes (1 ,ldinitrob enze ne is anelectron acceptor and c an be used asserotonin receptormodel) and showed M U of 7-S, ll, and 13-15 and un-substi tuted am phetam ine to be related as

MU = -3.798 + 7.918K

r = 0.97, F = 101.03 ( 7 )

For these a mp hetam ines native fluorescence was alsoshown qualitatively to be related with their MU val-u e ~ . ~ ~

However, for a bigger series of phenylalkylamines

(4-29) Barfknecht et aLmfound th at there exista a quitesatisfactory correlation between th eir hallucinogenicactivity and hydrop hobicity as shown by

log MU = -3.17 (f1.61) + 3.15 (k1.33) log P -

0.50 (k0.25) (log P ) 2

n = 26, r = 0.79, s = 0.41, log Po = 3.14(2.89-3.72)

(8)

In eq 8,Po is the pa rtition coefficient corresponding tothe o ptimum value of activity, and th e additional sta-tistical parameter s is the standard deviation, while

qua ntities within p arenthese s are 95% confidence in-terval. La ter, for almost the sam e series of com poun dsexcluding only 4,5, and 6 (taking only am phetamines),Kier a nd Halle4 correlated M U (molar basis) with atopological parame ter x known as m olecular connec-tivity as shown by

log mMU = 45.16 ( f7 .30) /3~p 1.288 (k0.20) 6xp-4.298 (f 0 .1 9) /4 ~ p 2 5.592 (f2.32)

n = 23, r = 0.920, s = 0.251, F3,19 = 35.0 (9)

where various xs are weighted counts of structuralfragments and represent the complexity of skeletalbranching in the molecule.a@ Obviously eq 9 expresses

a more significant correlation tha n eq 8. T he F value



W A R Studies on Hallucinogens Chemical Reviews, 1983, Vol. 83,No. 6 837

T A B L E 11. Various Phenylethylamines and TheirHallucinogenic Activity

c o mp d R MU"

4b 3 , 4 , 5 - (OC H, ) , 15 2 , 4 , 5 - ( O C H , ) , 16 ' 3 - O C H 3 - 4 , 5 - ( O C H , 0 ) 2

3 7 b 3 ,4 - (O C H , ) , < 1 ( 0 . 2 )

3 g b 3 , 5 - ( O C H , ) , - 4 - 0 C , H s 7

41' 2 , 5 - ( O C H 3 ) , - 4 - C H 3 2 042 ' 2 ,5-(OCH3), -4-Br 3543' 3 , 4 - ( O C H , O ) -144 2 , 3 , 4 - ( O C H , 3 <1

46' 2 , 5 - ( O C H 3 ) , - 4 - I 4 4

4 8 ' 3 , 5 - (OC H, ) , -4 -S C H3 1 2

36' 4 -OCH3 <1 0 . 5 )

3 8' 2 - O C H ,- 3 ,4 - (O C H 2 O ) < 5 ( 2 . 5 )

40b 3 , 5 - (OC H3 ) , -4 -OC , H, 6

45 2 , 3 , 4 , 5 , 6 - ( O C H , ) , d

47' 2 , 5 - (OC H, ) , -4 -C 2 H , 18

See re f 68 . Used in eq 13 . Used in eq 14 .Effec t ive human in tox ication leve ls have not been

evaluated fully.

in the former is significant a t 99% level (F3,19.01) =5.01).

Recently Dipaola et al.@ carried out model interactionenergy calculations for some phe nylethylamines using3-methylindole as receptor model, and observed thatthere exists a correlation between th e interaction energy( E )an d th e hallucinogenic activity of molecules. Th eyobtained the q uan titative correlations between E , cal-culated by Claverie an d R ein procedure67 for 17 com-poun ds (7-23), and log MU , as shown by

log MU = 0.31E - 0.89

n = 17 , r = 0.73, s = 0.21,F1,15

= 16.70 (10)

log MU = 0.28E - 0.2613,4 - 0.63

n = 17, r = 0.83, s = 0.17, F2,14 = 15.50 (11)

In eq 11,13,4s an indicator variable depicting thepresence of s ubs tituen ts a t positions 3 and 4 of the ring.T h e F values in eq 10 and 11 are significant at 99%level (F1,15 (.01) = 8.68; F2,14 (.01) = 6.51).

Kier's connectivity index (x) as further found to becorre lated w ith hallucinogenic activity of a sma ll seriesof mescaline analogues also. For the first ten com-poun ds of Tab le 11,the correlation obtained by Glennon

e t a1.68 wasMU = 129 3 ~ : - 4.45 4 ~ p 14.54

n = 10 , r = 0.97, s = 3.02 (12)

However, Gu pta et al.69were able to correlate MU ofthese com pounds with a single x of low order with alittle modification in the m ode of its calculation in orderto describe the stru ctur al influence on the a ctivity morevividly. In th is treat me nt, however, the whole series ofTable I1was found , when log MU was plotte d vs. x, obe distinctly separate d into two groups: lower groupcomprising of compounds with superscript b, and u ppergrou p comprising of those with supe rscript c. Fo r these

two distinc t groups, the correlations o btained were as

shown by eq 13 and 14, respectively

log MU = 0.758 'xu - 2.70

n = 6, 7 = 0.962, s = 0.209, F1.4 = 49.20 (13)

log MU = 0.668 'xu - 1.298

n = 8, r = 0.951, S = 0.251, F1,6 = 57.05 (14)

Eq 13 and 14 both ex hibit highly significant correlation.In bo th of them F values are significant a t 99% level

and 45 were not included in an y equation, as the exactMU values for them were not known. Th e separationof th e series into two groups in fact indicated tha t theremay be two receptor sites possessing sterically quitedissimilar natures, an d th at th e interaction of a mole-cule with a particular site might depend upon theconform ation of the molecule. Th e idea of the presenceof more than one receptor sites for a particular bio-logical action, in fact, has not been new. Th e serotoninitself is supposed to act at two different receptorsites,42p71)-72nd Bridger and Mende173have even sug-gested, based on their studies in intact animals, thatmescal ine, 3,4-dimethoxyphenylethylamine, ndam phe tam ine have different sites of activity.

(F1,4 (.01) = 21.20; F I , ~.01) = 13.74). Compou nds 44

2. Rabbit Hyperthermia and LSD-like Effects inAnimals

Th e rabb it hyperthermia assay has been employedin th e pharmaco logical evaluation of a series of LSDanalogues,M ubstituted tryptamine^,^^ and phenyliso-propyl amine^.^^^^^ An excellent correlation has been

found between hyperthermic and human poten-cies.5B-58i74 abl e I11 compares the hyperthermic po-tency of some phenylisopropylamines in sta nda rd rabbitunits (SRU)-activity expressed relative to 1-(2,5-di-methoxy-4-methylphenyl)-2-aminopropaneDOM, 24),which is assigned th e activity as 100-with hallucino-genic potency in MU. Howe ver, Anderson et al.58 e-ported t ha t hyper therm ic potency could neither be wellcorrelated with EHoMo or w ith log P. Th e correlationcoefficient obtained for the correlation between log SRUand EHoMowas only 0.65.

Gupta e t al.74however recently analyzed the dataobtained by Aldous e t al.56 (Table IV) in r elation tohydrophobicity con stant 7~ and th e steric parameter E ,

(Taft constant). In their treatment also,no significantcorrelations were initially obtained when all the dat apoints were included. However, when only (4-X-sub -stituted-2,5-dimethoxyphenyl)isopropylamines9-1 1,24-26,29, 58-60) plus th e 2,4,5-trichloro analogue (61)were treate d, both HT1 and H T2 (hyperthermic po-tencies ob tained by two d ifferent methods%) were foundto be significantly correlated w ith (sum of ?r valuesof substituents) as shown by eq 15 and 16, respectively.

log HT1 =

2.456 (0.523) ET 1.563 (0.282) (ET)' 0.566

n = 10 , r = 0.906, s = 0.468, F2,, = 16.00 (15)



63 8 Chemical Reviews, 1983,Vol. 83,No. 6 Gupta, Singh, and Bindal

TAB LE 111. Comparison of Rabbit Hyperthermic Potency of Some “Rearranged” Phenylisopropylamines with H umanPsychoto mim etic Potency and Elec tronic and Phys icochemical Parameterss8

c o m p d R S R U M U EHOMO,u E, V lo g P

3 5 -0 .410 7 .91 1 .75

TAB LE

89

1 02429495 05 1525 35 45 5565 1

IV .

2,4-(OCH,)z2,5-(OCH,),

2,5-(OCH3),-4-CH,3,4 ,5-(OCH,) ,

2 ,5 - (OC H2) , -4 -B r4;5-(OCH; j;2 ,4 - (OCH3),-5-CH,2-CH3-4,5-(OCH,),2,4-(OCH3),-5-SCH,2 ,5 - (OCH3),-4-SCH,2-SCH3-4,5-(OCH, ),2,4-(OCH3),-5-Br2 -B r -4 ,5 - (OC H3) ,H

Hyperthermic and LSD-like

3

1 21 0 04 0 5

0.31

0 .53

5 42231

8 -0 .409

16 -0 .39780 -0 .400

400 -0 .375< 1 -0 .419

-0 .403-0.407-0.409

50 -0 .4054 -0 .412

-0 .375-0.317-0 .473

7 .70 1 .72 , 1 .88

7 .66 1 .10 , 1 .747.62 2 .24, 2 .087.94 2.54, 2.588.03 1 .20, 1.00

2.241 . 7 62.17

7 .64 2 .171 . 8 12 .542 .06

8 .99 1 .63

Activities of phenyl isopropyl amine^^^ and Some Physicochemical Parameters

c o mp d R HT,a HTZa LSD-l ikeb z c ES(4ld

9 2 ,5 - (OC H,) , 0 .030 0 .025 3 .82 -0 .21 0.00i o 3 ,4 ,5 - (OC H, 3 0.036 0 .030 0 .20 -0 .5511 294 95-( OCH , ) 3 0.100 0.092 -0 .25 -0 .5524 2 ,5-(OCH3),-4-CH, 1.000 1 .000 0 .44 0 .31 - 1 .2425 2 ,5 - (0C H3) , -4 -CH, 2.290 2.220 0.38 0.76 - 1 .3126 2 ,5 - (OC H3) , -4 - (n -C ,H , ) 2 .370 2 .440 0 .073 1 .34e - 1 .6029 2,5-(0CH ,),-4-Br 4.0 50 3.010 0.064 0.81 - 1.1658 2 ,5-(OCH3),-4-CI 3 .770 3 .910 0 .75 0 .4 9 -0 .9759 2 ,5-(OC H, ) -4-( -C, , ) 0 .160 0 .080 1 .83 1 .19 -1 .7 160 2 ,5 - (OCH,) ,-4-( t -C,H,) 0 .142 0 .130 6 .96 1 .77e -2 .7861 2,4,5-C1, 0.006 0 .002 2 .05 -0.9762 3-OCH3-4-CH, 0 .052 0 .019 0 .64 -1 .2463 2 -OC H3-4 -C H, 0 .078 0 .051 23 .20 0 .19 -1 .24

64 3-OCH3-4-C1 0 .031 0.012 21.19 0 .82 - 0.9765 2-OCH, -4-C1 0.1 65 0.078 0.37 -0.9 7

61 4 -C H3 10 .78 0 .52 - 1.2468 4-C1 4.85 0 .70 -0 .9769 4 -B r 2.00 1.02 -1.1 6

66 2 ,4-C1, 0 .033 2 .05 1 .2 9 -0 . 97

(I Relative to DOM.56 Lowest dose (pm ol/kg ) producing des ired e ffec t .56 From Hansch, C .; Deutsch , E. W. Biochim.Biophys. A cta 1 9 6 6 , 126, 1 7 7 unless otherwise stated. From Martin, Y. C. In “Drug D esign”; Ariens, E. J., E d . ;Academic Press: N ew York, 1 9 7 6 ; V ol. VIII, p 2. e From Hansch, C .; L e o , A .; Unger, S. H.; Kim, K. H.; Nikaitani, D.;Lien, E. J. J. Med. Chem. 1 9 7 3 , 16 , 1207 .

log HT2 =

2.543 (0.646) ET - 1.679 (0.348) (ET) ’- 0.600

n = 10 , r = 0.884, s = 0.578, F2,7= 12.55 (16)In both eq 15 and 16, the F value was significant a t 99%level (F2,7(-01) = 9.55); the standard errors of thecoefficients of variables were given within parentheses.The LSD-like effect exhibited by this small set ofcompounds in rats was also found to be significantlycorrelated with ET but in combination with the s tericparameter of the 4-substituent (eq 17).

log (LSD-E) = 2.386 (0.914) CT0.682 ( 0 . 6 6 4 ) ( E ~ ) ~1.383 (1.047) E,(4 ) + 0.556

n = 8, r = 0.813, s = 0.572, F3,4= 2.59 (17)

Th e steric factor did not affect in any way the cor-

relations obtained between hype rthermic potencies andT . Th e trea tme nt of th is small group in isolation toothers was due to the fact tha t the substi tution at the

2- and 5-positions has been found to be very importantin psychotomimetic activities of phenylisopropyl-amines@- and that the substituent a t the 4-positioninfluences certain activities in a big way because ofsteric e f f e ~ t . ~ ~ . ~ ~

The correlations obtained between hyperthermicpotencies and LSD-like effect were as shown by

log (LSD-E) = 0.901 (0.184) log H T1 - 0.096

n = 11,r = 0.853, s = 0.482, F1.9 24.04 (18)

log (LSD-E) = 0.912 (0.163) log HT2 - 0.071

n = 10 , r = 0.892, s = 0.442, Fls = 31.18 (19)



QSAR Studies on Hallucinogens Chemical Reviews, 1983, Vol. 83 , No. 6 639

T A B L E V . Serotonin Receptor A gonis t ic Activ ityof Phenyla lkylamines

X

log logc o m p d R X R B R a P

4 3 , 4 , 5 - (OC H, ) ,

2 4 2 , 5 - ( O C H 3 ) , - 4 - C H ,2 5 2 , 5 - (OCH,) , -4 -C,H52 6 2 , 5 - ( O C H , ) , - 4 - n - C 3 H ,2 7 2 , 5 - (OCH,) , -4 -n-C4H,2 8 2 , 5 - ( O C H , ) , - 4 - n - C , H l l

3 9 3 , 5 - ( O ~ H , ) , - 4 - O C , H S4 0 3 , 5 - ( OC H3 ) , -4-O-n -C ,H,53 2 ,5-(OCH3), -4-SCH,60 2 , 5 - (OC H3 ) , -4 - t -C , H,

2 9 2 , 5 - (OCH3), -4-Br

7 0 3 , 5 - (OC H3 ) , -4 -B r7 1 3 , 5 - (OC H3 ) , -4 - i -C , H,72 2 , 5 - (OC H3 ) , -4 -B r73 3 , 5 - (OC H, ) , -4 -0 -n -C 4 H,747 5 2 , 5 - ( O C H 3 ) , - 4 - N O ,

3 ,5-(0CH , , 4-0CH C6H

a Reference 35 .

H 0.00

C H, 1.00C H , 1 . 5 9C H, 1 . 8 4C H, 1 . 6 2CH, 0.88C H, 1 . 5 7H 0 . 3 1H 0 . 5 6

0 . 7 8

2 . 2 42 . 7 63 . 3 74 . 0 04 . 4 32 . 5 41 . 1 11 . 7 0

CH , 1 . 3 1 2 . 1 7C H, 1 . 3 9 3 . 9 1H 0.88 2 . 0 3H 0 . 4 5 1 . 5 2H 0 . 8 3 1.81H 0.10 2 . 3 2H 0 . 4 8 2 . 4 0

C H, 0 . 6 7 1 . 7 4

3. Activity with Serotonin Receptors

Phenylalkylamines have been found to have directactions on serotonin receptors. However,QSAR studieshave been m ade only in very few cases. T he ir agonisticactivity (Table V) on th e serotonin recep tors of isolatedumbilical arter y prepara tion was shown by Nichols etal.35 to b e r elated with log P as

log RBR = 0.027 + 0.368 log P

n = 17 , r = 0.66, s = 0.44, F1,15= 11.86 (20)

Th is correlation was improved by inclusion of molarrefraction of par a subs tituen ts (MR,) in the regression(eq 21) bu t still better correlation was obtained with the

log RBR = 0.354 - 0.043MR4 + 0.501 log P

n = 17 , r = 0.81, s = 0.39, Fz,14 = 13.96 (21)

use of an indicato r param eter 14-indicating num ber ofatoms in para substituent-in place of MR4 (eq 22). I4

log RBR = -0.265 - 0.53914 + 0.595 log P

n = 17 , r = 0.926, s = 0.23, Fz,14 = 42.05 (22)

was assigned a value of 0 for compounds 4,24-26,29,

39,40,53,70-72,nd 75,l or 27 and 60, nd 2 fo r 28,73, nd 74.W ith the exclusion of com poun ds 73 and 74,which

were much less active tha n p redicted from th eir log Pvalues, Nich ols et al.35were however able to correlatethis agon istic activity of phe nylalkylam ines with qu itehigh degree of significance with log P alone, but theequation obtained was of third order (eq 23). In eq

log RBR =

0.23 - 0.89 log P + 0.95(10g P)' - 0.16(10g P)3

n = 15 , r = 0.98, s = 0.13, F3,11 = 77.86 (23)

20-23, RB R stan ds for relative biological response, and

represents the ratio of EDSO f mescaline to that of

compound. ThisRB R could be found additionally, byKier and G l e n n ~ n , ~ ~o be well correlated with x as

log RBR =

11.07 3 ~ p D 2.78(3~ ,U)z 6 .89 4 ~ p V 21.19

n = 17 , r = 0.95, s = 0.196, F3,13 = 39.6 (24)

Th e d ata on serotonin receptor binding affinity (PA,)for a small series of pheny lalkylam ines (T able VI) re-ported by Glennon et aLZ6were recently found76 o besignificantly correlated with s teric factors, such as va nder W aals volume V, (eq 25) or molar refraction MR(e q 26). V, and MR were however taken for ring

PAP = 2.174 (0.378) L V , + 5.196

n = 9 , r = 0.909, s = 0.265, F1,7 = 33.15 (25)

PAZ = 0.079 (0.013) C M R + 5.316

n = 9, r = 0.912, s = 0.260, F1,7= 34.70 (26)

sub stituen ts only. In fact, these parame ters for side

chain were not fou nd to affect the correlation in anyway. V , was calculated as suggested by Moriguchi etal.77 Compounds 4 and 80 were not included in theregression, as they fell quite far from th e least-squ areline.

B. Indolealkylamines

Indolealkylamines are least studie d for their hallu-cinogenic activity, but th ey a re however comp arativelywell studied for their actions on serotonin receptors(vide section 111). Th e da ta on binding affinity (PA,)of several tryp tam ine analogues for serotonin receptorsof ra t stomach fundus strip have been obtained. Si-multaneous attempts have been m ade to correlate themwith molecular orbital (MO) and hysicochemical pa-

few of th e da ta obtaine d by themselvesz5with MO pa-ram eters calculated with the use of A (PPP-SCF)as wellas all valence-electron (CNDO/2) methods.59 For th eda ta given in Table VII, the correlation equations ob-tained were

rameters. Glennon and Gessnerz5 ried to correlate a

PPP-SCF results

PAZ = 10.24f4E+ 4.56

n = 9, r = 0.60, s = 0.496 (27)

pA 2 = 15.47f4E+ 3.90

n = 8, r = 0.96, s = 0.159 (28)

pAz = -16.87fGE + 7.54

n = 9, r = 0.94, s = 0.209 (29)

PA2 = 5.90fsN+ 5.30

n = 9, r = 0.53, s = 0.525 (30)



Gupta, Singh, an d Bindal40 Chemical Reviews, 1983 , Vol. 83, No. 6

T A B L E VI. Serotonin Receptor Binding Affinity of Phenylalkylamines and Steric Parameters

-___

____-___o m p d R --x I?Ur(R) c M R (R)' p A z b

4 3 ,4 ,5 - (OC H,) , C H,NH, 0 .912 23 .61 5 .659 %5-(OC H,) , CHCH,NH, 0.664 16.77 6 .83

1 1 2 ,4 ,5 - (OC H3) , CHCH,NH, 0.912 23.61 6 .8115 3,4-( OCH ,O) CHCH,NH, 0 .406 9 .99 6 .45

24 2 ,5-(OCH,) ,-4-CH3 CHCH ,N H , 0.853 21.39 7 .12

7 6 2 , 5 4 0 C H 3 ) , C H ,N H , 0.664 16 .77 6 .8577 H CH,NH, 0 .168 3 .09 5 .267 8 2 , 5 - ( O C H , ) , C H,N(C H,) , 0 .664 16 .77 6 .5279 2 ,5-(OCH3 CHCH,N(CH,) , 0 .664 16 .77 6 .50

29 2 ,5-(OCH3),-4-Br CHCH,NH, 0 .951 25.65 7 .35

80 2 ,5-(OCH ,) , CH ,CH,N( CH 1, 0 .664 16 . 77 5 .45

a From : Hansch, C.; Leo, A . ; Unger, S. H.; K im, K. H.; Nikaitani, D .; Lien, E. J. J. M e d . C h e m . 1973, 6, 1 2 0 7 .References 26 and 53.

T A B L E VII. Serotonin Receptor Binding Aff in ity o fN,N-Dia lk yltryptamin es and Related

,Ch2!IURI

c o mp d K X R R ' PA ?a

81 2 NH H CH, 6 .0082 2 NH 5-OC H3 CH, 7 .1083 2 NH 4-OCH3 CH, 6 .178 4 2 NH 5-COCH, C H, 5 .8685 2 NH 6-OC H3 CH, 5.7786 2 NH 7-OC H3 C H3 5 .33

88 3 NH H CH389 2 s H CH390 2 NH H CZH,

87 2 NH 5 -OH C H, 7 .416 .006 .035.79

91 2 NH 6 -OC H3 C ,H , 6 .9492 2 NH 5 -OC H3 n -C ,H , 6 .539 3 2 CH, H CH, 5 .68

a Ta ke n f rom ref 53 .

CND0/2 resul ts

pA 2 = 11.46f3E+ 1.25

n = 6 , r = 0.82, s = 0.424

pA 2 = 17.37fdE+ 2.63

n = 6, r = 0.73, s = 0.499

(31)

(32)

n = 5, r = 0.76, s = 0.417 (33)

PA, = -16.60feE + 9.36

n = 6, r = 0.80, s = 0.457 (34)

In the PPP-SCF results, how ever, were included onlyNfl-dimethyl t ryptamine (DMT, 81 ) analogues 81-89and in the CNDO/2 results only methoxy derivativesof DMT (81-86) were included. Besides, 86 was notincluded in deriving eq 28 and 33. The MO parametersf r E and f r N ( r = 1, 2, ...) occurring in these correlatingequations are in general the electrophilic and nucleo-philic frontier orbital electron densities a t position r ,respectively. No other para meters, not even the m ost

expected ones-EHoMo and ELmo energy of the lowest

unoccupied M0)-were found to be correlated withpA2. H owever, eq 27-34 have also not been conclusive,as he number of data points used have been very small.

Green an d Kang17 analyzed the activity data o btainedby Vane2' for a series of ring-su bstituted tryptamine s

on the same LS D/serotonin receptor m odel in relationto MO parameters calculated by INDO approximation.The activity was expressed in terms of Cs0, he con-centration of the drug relative to serotonin giving acontraction of 50% maximum to the rat fundus. Later,however, Johns on and Green7*extended the d ata set(Table VIII) and correlated them with MO parametersobtained by CNDO/2 method, and hydrophobicityconstant T . Th e significant correlations th at surfacedwith exclusion of compounds 96 and 104 from regressionanalysis were as shown by eq 35-40. In these equations

log (l/Cbo) = 14.35flE + 1 .572~7 3 .734

n = 15 , r = 0.926, s = 0.399, F2,,,= 43.1 (35)

log (~ /CM) 10 .55f4E+ 1 .948~7 3 .139

n = 15, r = 0.811, s = 0.618, F2,12 14.5 (36)

log (1/Cm) = 18.09flE- 74.77q1 + 1 .1 82~ 7 13.061

n = 15, r = 0.962, s = 0.288, F3,11 = 59.4 (37)

log ( l / C w ) = 24.36fdE- 188.4Oql + 1 .4 10 ~7 27.464

n = 15 , r = 0.935, s = 0.375, F3,11 = 33.4 (38)

n = 15, r = 0.958, s = 0.304,F,,,, = 52.6 (39)

log (l/cw) = 24.12fdE- 9.451q7 + 1 . 3 0 0 ~ 7 5 . 40 5

n = 15 , r = 0.927, s = 0.395, F3,11 = 29.7 (40)

qr ( r = 1, 2, ...) represents the ne t total charge on atomr and 7r7 the hyd rophobicity cons tant of the su bstituentat the 7-position. All these equations expressed sig-nificant correlations-the F value in all of them is sig-nificant at 99 % level (F2,12(.01) 6.93; F3,11(.01) 6.22 ).However, since it was not clear to Johnson and Green

how th e ring carbon w ould be involved in electron do-



QSAR Studies on Hallucinogens Chemical Reviews, 1983, oi. 83,No. 6 641

TABLE VIII . Potencies of Tryp ta m ine s on I s o lat e d R a t Fund us S t r ip , MO Pa ra me te r s, a nd Hydrophob ic i ty C ons ta n t7*

. d H 2 N H 2

H

~ ~~ ~~~~~~~ ~

lo gc o m p d R (1/c50)a q1 q 6 q7 f l E f4 E = 7

2 a H - 1 .1 7 - 0 . 1 1 8 8 - 0 . 0 1 3 8 - 0 . 0 2 3 1 0 . 1 5 8 5 0 . 1 5 0 52b 5-OH 0.00 - 0 . 1 1 6 8 - 0 . 0 3 9 7 - 0 . 0 0 0 4 0 . 2 3 8 4 0 . 2 2 2 8 0.00

94 5 -OC H3 -0 .06 - 0 . 1 1 6 7 0 . 0 40 4 - 0 . 0 0 1 8 0 . 2 3 2 5 0 . 2 1 5 395 5 -OH-7-C l -0 .16 -0 .1131 - 0 . 0 3 3 1 0 . 0 7 1 7 0 .1951 0 .2107 0.809 6 5 ,6 - ( O H ) , - 0 . 4 2 - 0 . 1 1 8 0 0 . 1 5 3 5 - 0 .0 6 6 5 0 .0335 0 .03609 7 5 4 1 -0.88 - 0 . 1 1 8 1 0 . 0 2 0 3 - 0 . 0 2 2 9 0 . 1 9 0 1 0 . 1 7 4 19 8 5 - CH 3 - 0 . 9 5 - 0 . 1 1 8 0 - 0 . 0 0 4 2 - 0 . 0 1 6 9 0 . 1 8 5 5 0 . 1 7 4 39 9 5 - F - 0 . 9 8 - 0 . 1 1 6 2 - 0 . 0 4 1 5 - 0 . 0 0 1 5 0 .1926 0 .1767

100 4 - O H - 1 . 1 5 - 0 . 1 1 9 0 0 . 0 3 7 1 -0 .0521 0 .1434 0 .14541 0 1 4 - N H, - 1 . 5 4 - 0 . 1 2 0 0 0 . 0 2 9 7 - 0 . 0 4 6 0 0 . 1 3 8 1 0 . 1 4 9 8102 7 -OC H, -1 .70 - 0 . 1 0 8 9 - 0 . 0 5 8 8 0 . 1 6 3 8 0 . 1 7 6 1 0 . 2 0 7 0 - 0 . 2 1103 5 ,7 - (OC H3) , -1 .86 - 0 . 1 0 6 8 - 0 . 1 1 4 2 0 . 1 8 4 3 0 . 1 9 8 1 0 . 2 4 5 2 - 0 . 2 110 4 5 ,6 - (OC H3) , -2 .17 -0 .1194 0 .1510 - 0 . 0 7 7 4 0 . 0 2 0 6 0 . 0 2 1 41 0 5 6 -O H - 2 . 50 - 0 . 1 2 1 6 0 . 1 9 9 2 -0 .0869 0 . 0 8 6 6 0 . 0 9 3 71 0 6 6 - O C H 3 - 2 . 9 8 - 0 . 1 2 0 8 0 .1991 - 0 . 0 9 6 3 0 . 0 8 0 4 0 . 0 8 6 21 0 7 5 , 6 , 7 - ( 0 H ) , - 3. 0 7 -0 .1112 0 .0862 0 .1314 0 . 1 3 9 0 0 . 1 8 7 3 - 1 .0 71 0 8 5 , 7 - ( O H ) , - 3 . 0 9 - 0 . 1 0 8 1 -0 .1151 0 .1862 0 .2010 0 .2530 -1 .07

a C,, s the conc entra t ion of the drug re la tive to serotonin giving a contrac t ion of 5 0% max imum to t he ra t fundus s t r ip .

TABL E IX. Serot onin Uptake Inhibi t ion Act iv ity ofTryp ta m ine De r iva tivesRdHzNR

H

lo gc o m p d R N R , R l ED,: P a E T P P

94b9 6 b

1 0 0 ;

1 0 1103 '1 0 5 b1 0 8 b1 0 9 bl l O b

111'

112 '113'1 1 4 b1 1 5 b1 1 6 b117 '11V119 '1 0'1 2 1 b

1 2c123 '1 4'

36 .0 1 .4422 .5 0 .721 2 . 0 0 . 7 9

1 2 . 5 0 . 2 39 . 5 1 . 4 2

1 9 . 0 0 . 7 948 .5 0 .121 8 . 0 0 . 7 935.4 0 .79

1 . 9 1 . 3 53 .5 2 .008.0 2.44

4 6 . 0 1 . 9 126 .0 1 .354 2 . 5 1 . 2 4

9 .3 2 .546 .0 1.819.0 2 .469 .0 1 .98

84 .0 2 .83

7.5 2 .271 8 . 0 3 . 4 830.0 3 .46

32 .15632 .42228 .806

26 .29840 .51028 .79632 .42628 .12830 .41032 .23036 .2784 4 . 6 1 43 6 . 3 3 03 4 . 4 9 640 .6304 8 . 7 0 43 6 . 2 3 240 .27248.61248 .620

42 .48048 .35656 .694

a R e fe re nc e 71 . Fo rming uppe r g roup . ' orminglower group.

nation , they professed eq 37 to be the m ost meaning-f ~ l , ~ ~houg h later W einstein e t al.79 established th econsiderable contribution of C4-C, and th e importanceof bridge region to the overall electrostatic reactivitypattern of biologically active indolealkylamines.

Kumbar et al.71 tudied th e serotonin-uptake inhib-ition activ ity of a fairly large series of try pta m ine s inthromb ocyte an d correlated the ED, (effective dose

producing50%

inhibition) with to tal orbital energy

(TOE ) and th e hydrophobicity factor log P. Later,Gupta e t al.72correlated it with V,. However, bothgroups of wo rkers had found th at on t he p lot (activityvs. relating parameters), th e series as listed in Table IXwas divided into two d istinct g r o ~ p s : ~ ~ ~ ~ ~he uppergrou p comprising of com poun ds with superscript b andthe lower group comprising of those w ith super scrip tc. For the upper group, the significant relating equa-tions obtained by Kum bar et al.'l were

log ,ED, = -2.952 + 2.908 log TOE

n = 12 , r = 0.851, s = 0.134

log ED50 = 1.215 + 0.223 log P

(41)

n = 12 , r = 0.650, s = 0.190 (42)

3.368 (f0.939) log TOE -0.055 (k0.094) log Plog ED, = -3.581 (h0.038) +

n = 12 , r = 0.856, s = 0.132

log ED, = O.928Vw+ 0.826

(43)

Th at obtained by Gupta et al.72was

n = 12 , r = 0.791, s = 0.164, F I , ~ ~16.73 (44)

Similarly for th e lower group the corresponding equa-tions were

log EDm = -5.539 + 3.954 log TOE

n = 11 , r = 0.893, s = 0.142 (45)

log ED, = 7.899 X + 0.361 log P

(46)

2.324 ( f0 .842 ) log TOE

+0.226 (*0.092) log P

n = 11 , r = 0.801, s = 0.189

log ED, = -3.275 (A0.033) +



64 2 Chemical Reviews, 1983, Vol. 83 , No. 6 Gupta. Singh, and Bindal

TAB LE X . Dis p la c e me n t of [3 H ]Se ro ton in a nd [3 H ] L S Dfrom R a t C e reb ral C o r t e x Me mbra ne s by Va r ious Drugsand Log P Valuesa

lo g U/ I C50)

[ 3 H ] - [ 3 H ] -n o . c o m p d 5 H T L S D l o g P

2a2b

8 18 794

9 61 0 8

3a3 b3 c3d

I C

I d1 2 51 2 61 2 7

1 2 8

Tryp ta mine st ryp ta mine 6 .00 5 .705-HT 8.00 6 .00

D M T 5 . 7 0 b 5 . 7 05-HO-DMT 7.70 6 .525-me thoxy t ryp ta mine 7 .30 6.005 ,6 -d ihydroxy t ryp ta mine 6 .22 5 .155 ,7 -d ihydroxy t ryp ta mine 5 .00 4 .5 2

LSD 8.00 8 .102 Br -LS D 7 .00 8.00i solysergic ac id amide 7 .00 6 .70methylsergide 6 .52 7 .00

nore p ine phrine 3 .52 3 .00dopa mine 4 .40 4 .22f luphe na zine 5 .70 7 .00c h lo rp roma z ine 4.30 7 . 0 0prome tha z one 6 .00

haloperidol 5 . 7 0 b

LSD A nalogues

Neur otransm it te rs and Analogues

0.880 .21

1 . 7 81 . 1 00.81

- 0 . 3 7- 0 . 4 5

2 .953 . 8 10 . 9 52.34

- 1 . 2 4-0.98

4 .365 .354 . 7 3

4 .30

* R e fe re nc e 80. Not used in regressions.

n = 11, r = 0.938, s = 0.109 (47)

log ED, = 1.093Vw- 0.244

n = 11,r = 0.890, s = 0.152, Fl,g= 34.46 (48)

On the basis of th e sepa ration of com pounds into twodistinct groups, i t was therefore proposed that theremig ht be involved two recepto r sites of a sterically, ifnot electronically, dissimilar nature in uptake of sero-

tonin.Tryptam ines and some other drugs (Table X ) werefound to displace specifically bou nd [3H]serotonin and[3H]LSD rom ra t cerebral cortex memb ranes.32 Chane t aL80reported th e displacemen t of binding d ata (IC,- he molar concentration required for 50 % displace-me nt) to be significantly correlated w ith log P in themanner as shown by eq 49 for [3H]serotonin and by eq50 for [3H]LSD . Some [3H]LSD displacement data,

log (l / IC50 ) = 1.391 log P - 0.330 (log P ) 2+ 6.181

n = 14, T = 0.873, s = 0.766, log Po =2.11 (1.76 - 2.52) (49)

log (l / IC50 )= 1.222 log P - 0.182 (log PI2 + 5.265

n = 16 , T = 0.906, s = 0.613, log Po =3.36 (2.77 - 4.83) (50)

e.g., tho se of Gree n e t a1.81 on m escaline, LS D, an d afew amphetamine and tryptamine derivatives, andthose of Ben nett and Agha janiad2 on a sma ll series ofsimilar compounds including some phenothiazinetranquilizers, were show n by Dom elsmith an d HoukGOto be related with ionization potentials also (eq 51 and52, respectively, wh ere IP1 represe nts f irst ionizationpotential and IP z second ionization potential, measu redby photoelectron spectroscopy62% In these equations

TABLE XI. Rela t ionship of Hallucinogenic Activity( M U ) of Different Classes of Hallucinogens with EHOM0I4

EHOMO?no . c ompd M U R

3a LSD 3700 0 .21844 mescaline 1 0 .5357

1 0 3 ,4 ,5 - t r ime thoxya mphe t - 2 .2 0 .5357

11 2 ,4 ,5 - t r ime thoxya mphe t - 17 0 .4810

129 4 -HO-DMT 31 0 .46031 3 0 6-hydroxydiethyltryptamine 25 0 .4700

a Hiickel values.

a mine

a mine

-log IC, = 47.78 - 3.81IP1 - 1.64IP2

n = 10 , r = 0.85 (51)

n = 7, r = 0.97 (52)

ICsorepresents t he inhibition constant for high affinityLSD binding in ra t brain homogenates.

Howe ver, the scantly available hu man or anima lqualitative d ata o n psychotropic activity of thes e in-dolealkylamines were not found to have a ny relationwith any electronic parameter reflective of either ageneral or localized cha rge -tran sfer process,&l n spiteof the fac t tha t Karreman et al.13 and Snyder andMerril14 stres sed th at , irrespective of the ir class, thehallucinogens exert their psychomimetic effects throug hthe fo rmation of ch arge-trans fer complexes with thereceptors, and the qualitative observation of Sny der andMerril (Table XI) being well sub stan tiated by qua nti-tative analysis by G upta a nd Singhs5 (eq 53).

log MU = 5.956 - 1 0 . 2 5 9 E ~ o ~ o

n = 6, r = 0.972, s = 0.327, F1,*= 68.81 (53)

C. Lysergic Acid Derlvatives

Lysergic acid derivatives or LS D analogues have beencomp aratively well stud ied for their antiserotonin andhallucinogenic a c t i v i t i e ~ , ~ ~ ~ ~ * ~ ~ * ~ ~ - ~nd the da ta tha twere available was subjected to QSAR studies. How-ever, as in the case of tryptam ines, Kum bar a nd SivaSankar91v92ailed in their attem pt to correlate them withany electronic param eter reflective of ch arge-trans ferprocess apparently, rather they found a correlation withTOE. With th e use of da ta as given in Ta ble XII, theseauth ors showed the hallucinogenic activity (H)o berelated with TOE asg1

log H = -11.8596 + 7.3951 log TO E

n = 12 , s = 0.4003 (54)

and antiserotonin activity ( a n t i 4 and TO E are relatedasg2

log (anti-S) = -2.7092 + 0.07955TOE

n = 15 , s = 0.2715

log (anti-S) = -16.2811 + 10.2838 log TO E

( 5 5 )

n = 15 , r = 0.889, s = 0.2709 (56)




T A B L E XII . Antiser otonin a nd Hal luc inogenic Act iv it ies and Hiickel's Tota l MO Energy of LSD an d i ts Analogues

Chemical Reviews, 1983, Vol. 83 , No.6 64 3

O\C/NRIRz

I

R 3 R 4

c o m p d NRlR2 R3 R, anti#' Ha TOE,^ p

3a N(C2Hs 12 H H 1 0 0 1 O d 58 .25061 .294b N(C ,Hs) , H B r 15 0 7 .2,d < 242 .292

H 4 0 0 0 . 6 6 3 . 2 9 4H 6 . 3 4 6 . 1 8 8

H H 23 .2 10d ,e 50 .262H 11.9 5 ,d 3 .4e 50.180H 8 35 ' 4 d 5 e 5 4 . 2 2 8H 3 9 $,e 59 .75635 NHC ,H, C OC H,

136 NH( iC ,H7) H H 22 .2 51 .024H 36 8 36 ,d 40e 62 .294H 58.9 66d3e 63.7 1838 N(C,Hs 12 OCH,

13 9 N(C ,Hs ) , C OC H, H 21 0 100 ,d 91e 67 .8241 4 0 N ( C 2 H 5 ) 2 H I 57 .4 59 .516

Br 53 3 <1 65 .352H 1 3 0 < 5 6 2 .5 0 2H 4.7' 5.3,d l o e 58 .440

1 4 4 N ( CH,-CH= CH-CH,-) H H 4.1' 10dse 52 .9 681 4 5 N(-c 5H10-) H H 8.5 ' 62 .44 21 4 6 N(-C,H,-0-C,H,-) H H 8.0' 11dpe 62 .728

H H 4 . 3 03c NH,3d NH[C H(C ,H , )C H,OH] C H,

1 3 1 N H C H , H

1 3 3 N H C ,H , H

13 4 NHC ,H, C H,

137 N(C ,H , ) , C H3

1 3 2 N ( C H 3 ) 2

1 4 1 N ( C 2 H S ) 2 CH31 4 2 N(-C,H,-) CH,1 4 3 N(-C,H,-) H

a Da ta c o l le c te d by Kumba r a nd S iva Sa nka r ,91 '92rom ref 70a, 87, 88, an d 90 ; al l ac t iv i t ies a re re la t ive to t ha t o f LSDR e fe re nc e 92 . ' ot included in regression analysis . d Used to obta in eq 54. e Us ed t o ob ta in e q 58aken as 100.

a n d 6 0 .

T A B L E XIII. Ant i s e ro ton in Ac t ivi ty a nd H ydrophob ic i ty in their study Gup ta et found tha t both activit iesof Side-Chain Only Subs t i tu ted LSD Analogues were, to a great extent, the function of the size of

side-chain substitue nts (NR1R2)and thus th e correla-tions expressed by eq 57 and 58 could be only slightlyimproved by inclusion of V, of the R 3 substi tuent(compare eq 57 with 59, and eq 58 with 60) and werehardly affected by the inclusion of V of the R4 sub-

log (anti-S) = 2.793 (0.401 ) V,(NR,R2) - 0.032

n = 15 , r = 0.888, s = 0.311, Fl,13 48.49 (57)

O\C/NR1R2

&-CH3 sti tuent.

HN

lo gc omp d NR ,R Z (a n t i+ )= log P b

3a

3c

1311 3 21331361 4 3

1 4 41 4 51 4 61 4 71 4 81 4 91 5 01 5 11 5 2

N ( C 2 H 5 ) 2 2 .00 2 .16NH. 0 .63 ' 0 .16N H ~ H ,

N ( C H 3 ) 2

N H C 2 H 5NH(1'-C,H,)

N(--C,H*-- )

N(-CH2-CH=CH-CH,-

N(-C,H,-O-C2H,-)NHC,H,NHC,H,

( 5 10- )

NH(CSH1,)

N(i-C,H 7 1 2

N(C,H,) ,

N ( C 3 H 7 ) 2

0.81' 0 .661 . 3 6 1 . 1 61.08' 1 . 1 61 . 3 50 .67 1 .76

-) 0 . 6 1 1 . 5 60 .93 2 .160 . 3 1 0 . 2 21 .60 ' 1 .601.81 ' 2 .161.87' 2.661 . 6 2 3 . 1 61 . 3 71 .49 4 .16

log H = 2.686 (0.658) Vw(NRIRJ - 0.612

n = 10, r = 0.822, s = 0.289, F1,8= 16.65 (58)

log (anti-S) = 2.536 (0.388) Vw(NRlR2)+1.120 (0.581) Vw(R3)- 0.056

n = 15 , r = 0.916, s = 0.283, F2,12 31.17 (59)

log H = 2.474 (0.503) Vw(NR1R2)+1.267 (0.477) Vw(R3)- 0.716

n = 10, = 0.916, = 0.218, F 2 , 7 = 18.14 (60)

C e re le t ti a nd Doe pfne r da ta s 7 us ed by D unn a ndB e de rka g4 nd G le nnon a nd K ie r .95 R e fe re nc e 94 .' s ed by Kumb a r a nd S iva Sa nka r to ob ta in e q 58.

Th e antiserotonin and hallucinogenic activity data werehowever also foun d to be significantly correlated with

the size of the Substituents accounted for by Vw,93and

In agreem ent with the findings of G upta et al., someof th e C ereletti and Doep fner datas7 on antiserotoninactivity of side-chain only substituted LSD analogues(Table XIII) were showng1 o be related with num berof carbo n atom s N in the alkyl substituent as shown by

ant i -S = 1/(0.01185 + 0.2207 e-N) (61)



Vol. 83,No. 6 Gupta, Singh, and Bindal44 Chemical Reviews, 1983,

T A B L E XIV. Toxic ity and Pyretogenic Activity of Some L SD Analogues

O\C/NR,R,

I

3b H1 3 2 N ( C H ,L H133 NHC,Hi H

1 3 4 N H C , H , C H ,

13 7 N(C,H,) , CH,

1 4 1 N ( C , H , ) , C H31 4 2 N (-C4H I-) CH3143 N(-C,H 8- 1 H1 4 6 N( C ,H,-O--C,H,- ) H

135 NHC,H, C OC H,

139 N(C ,H , )* C OC H,

a See ref 91. N o t used to obta in corre la t ing equat ions ( e q 6 6 a n d 6 7 ) .

R4 log TCa lo g PG a

Br 0 .699 0 .69 9H 1 . 8 9 2 1 . 6 3 4H 1 . 5 3 2 b 1 . 2 3 0H 0 . 5 0 5

H 0 . 7 4 8 0 . 6 9 9H 1 . 2 7 9 1.114bBr 0 . 3 0 1 bH 0 . 6 0 2H 1 . 8 6 3 1.000H 1 . 6 3 4 1.000

H 2.000b 2.000

H 0 .778 0 .000b

Eq uation 61 was in fa ct obtained only for side-chainmonoalkyl subs tituted analogues excluding 136. For allsuch m onoa lkyl-substituted analogues including even136, the Cereletti and D oepfner data were found to becorrelated with V , asg3

log (anti-S) = 1.789 (0.173) V,(NR,R,) + 0.282

n = 7, r = 0.977, s = 0.113, F1,5 106.38 (62)

How ever, for both mono- a nd dialkyl side-chain-sub-sti tuted analogues, these antiserotonin data as men-tioned in Table XI11 were shown by Dunn an d Beder-

kag4 o be significantly correlated with log P, and byGlennon and K ierg5with x, as shown by eq 63 and 64,respectively. In both eq 63 and 64, RBR sta nd s for

log RBR = -0.54 (f0.32) - 0.74 (f0.28) D +0.84 (f0.35) log P - 0.14 (k 0.08 ) (log P)'

n = 14, r = 0.94, s = 0.20, log Po = 2.90 (2.40 - 4.32)

(63)

log RBR = 24.94 (f3.9) - 0.835 (f0.033) 'X -0.917 (k0.083 ) 6 ~ p 1/0.0072 (f0.004) O x u

n = 16 , r = 0.940, s = 0.196 (64)

relative biological response a nd was used by these a u-thors in place of anti-S. Further in eq 63, D is a dummyvariable used t o account for am ide nitrogen being en-closed in a ring system. It was assigned a value of 1 famide n itrogen was p ar t of cyclic system, otherwise itsvalue was 0. In th e derivation of eq 63, however, com-pounds 13 6 and 151 were not included.

With the use of data of Tab le XII, a mutual corre-lation was shown to exist between hallucinogenic an dantiserotonin activities of LS D analogues by Siva San-kar and Kumbarg2 s

log (H/anti-S ) = 1.1614 - 1.1093 log ( a n t i 3

s = 0.6499 (65)

Finally, the toxicity (T C) and the pyretogenic activity(P G) of som e LSD analogues (Table XIV) have alsobeen reported to be correlated with V, as shown by eq66 an d 67, respectively.%

0.996 (log TC)' - 2.262 log TC + V, + 0.044 = 0

n = 9, r = 0.901, s = 0.103, F2.6 = 12.95 (66)

0.960 (log PG)' - 2.784 (log PG) - V , + 2.628 = 0

n = 7, r = 0.973, s = 0.060, F 2 , 4 = 36.23 (67)

V. Dlscusslon

From these QSAR stud ies, the f irst impression tha tis created is tha t among the various factors that maybe responsible for physiological and pharmacologicalactions of hallucinogens the electronic prope rties playdom inant role. However, the idea that these drugs xerttheir hallucinogenic activity through the formation ofcharge-transfer complexes with th e receptors, in whichthey act as donor, could not be firmly established. Th ereasons are(1)The correlations that have been obtained between

the activity and the electronic factors reflective ofcharge-transfer processes have neve r been tota lly freefrom criticisms. For examp le, neither eq 1nor 2, ob-

tained by Shulgin et al.,52 epresents any highly sig-nificant correlation between the activity and EHOMOeven though only 13 compounds were treated, whileactivity d at a were available for a large series of com-pounds. Besides, EHoMo was not able to account for theactivity of all compounds treated.52 Similarly eq 3,showing th e correlation between activity and observedionization potential, was obtained only for 11 com-pounds, excluding the most potent one, 2,5-dimeth-oxy-Cbromoamphetamine (29). Th e ionization poten-tial was not able to account for the activity of this

compoun d, and even for those co mpound s fitting eq3,



QSAR Studies on Hallucinogens Chemical Reviews, 1983, Vol. 83 , No. 6 645

there were some notable d eviations, e.g., com poun ds 11and 24 have almost equ al ionization potentials b ut thereis a large difference between their ac tivities. In a recentcommunication also, Domelsmith and co-workersg7showed that ionization poten tial alone was not sufficientt o accou nt for the hallucinogenic activity of a mp het-amin e analogues. Anomalies were found in the d ata ofAn tun e t al. on UV fluorescence,5l in Bailey and V er-ner’s data on W abs0rption,4~ nd in Sung an d P arker’s

da ta on stab ility of charge-transfer complexes,s0henceneither eq 5 and 6 nor eq 7 included all data pointsstudied. Th us, they were obtained for a very smallnumber of d ata po ints, such as 6 and 8, respectively,and on inclusion of all data p oints they showed verypoor ~ o r r e l a t i o n s . 4 ~ ~ ~oreover, Sung and Parker madetheir s tudy on ch arge-transfer complexes using a modelreceptor and not the true serotonin receptor, as didDiPao la et a1.66 n the ir mo del interaction en ergy cal-culation. T he param eter E appea ring in eq 10 and 11represents, as already mentioned, interaction energybetween a phenylalkylamine and 3-methylindole usedas a rece ptor model.

(2 ) Correlations between h allucinogenic activity a nd

electronic parameters reflective of charge-transferphenom ena were m ostly obtained for only one class ofhallucinogens, e.g., phenylalkylamines.

(3) Though the activities, like serotonin receptorbinding affm ity, and abilities to contract LSD/serotoninreceptor a nd displace specifically boun d [3H ]serotoninand [3H]LSD from ra t cerebral cortex memb ranes ofindolealkylamines have be en found t o be related w ithelectronic param eters (vide section IVB),hey have notbeen shown to hav e any direc t relation with their hal-lucinogenic activity.

(4) The validity of such structure-activity relation-ship studies is sometimes challenged on the basis tha tthe biological data used for the correlations with mo-

lecular struc tur e do not necessarily reflect the efficacyof th e dr ug on its biological receptor b ut a re a compositeof many events including the various stages of drugtransp ort , uptake , metabolism, an d excretion.

However, the role of electronic facto rs in hallucino-genic drug-receptor interaction canno t be completelyruled o ut. B ut G lennon a nd G e ~ s n e r ~ ~ ~ointed out,particularly in the case of indolealkylamines, that ageneral charge-transfer mechanism may no t be involved,bu t ra ther a localized charge-transfer phenomenon maybe implicated. The se authors had failed in their at-tem pt to correlate binding affinity da ta (PA,) of tryp-tamines with E H O M O , bu t obtained eq 27-34, on thebasis of which they suggested tha t electron d onation

might occur in a localized manner from the 4-positionof tryptamine s. Although fsE (electrophilic frontierorbital electron d ensity a t the 6-position), obtained byPPP as well as C N D 0/ 2, was also found to be signifi-cantly co rrelated with pA 2 (eq 29 and 34) but, sincecoefficient was negative in both the correlating equa-tions and thereby implied that as electron-donatingcapab ility at the 6-position increased pA 2 would de-crease, Glennon and Gessner did not assign any im-portance t o this position, nor did the y argue in favorof electron donation from the 3-position,as 3E obtainedby C N D 0 / 2 only was foun d to be correlated w ith pA2.

However, as a ma tter of fact, none of the equationsobtained by Glennon and Gessner was very convincing,

since eq 27-30 were derived with the use of data ob-

tained by the PPP me thod , which involves several ap-proximations, a nd eq 31-34 were obtaine d for suc h asmall number of data points that it was difficult toassociate a ny significance to them , though electronicda ta were obtained by a refined m ethod, i.e., CN D 0/2 .fd E alone was found to have no correlation w ith LSD /serotonin receptor contraction ab ility of tryptamine^,^^and although in combination with r7and q1 or q7,andwith the exclusion of com pounds 96 an d 104 from Table

XIII, some significant correlations were obtained (eq38 and 40), it was not clear to Johnson and Green7showring carbon would be involved in electron donation, norcould they find a n explanation as to why potency wouldincrease either by increasing the negative charge a t the7-position or by increasing the hydrop hobic nature ofthe substituent a t this position. Therefore, in their vieweq 37 was the m ost meaningful. r7 , l , or q7 individuallywere not found to be significantly correlated with th eactivity. However, We instein e t al.79 ater establishedthe importan ce of th e en tire C4-C5 bond region. Ac-cording to these authors tryptamines form polariza-tion-type complexes with th e receptor, and the sites ofmaximal polarizability in the indole portion of the

tryp tam ines form the reactivity criteria. Thes e sites ofmaximal polarizability were shown to be directly relatedto th e localization of the highest occupied molecularorbital (HOMO ) in the molecules. Th e highest con-tribution to the polarization term in the interactionenergy comes from the highest occupied molecular or -bital (HOMO) and a t the centers at which the densityof HOM O is localized. How ever, the pa ttern s oflocalization of HOMO ’S were fo un d to be dif fere nt indifferent tryptam ine congeners, and that was one of thereasons for the app aren t failure to find a direct corre-lation of biological activ ity with EHOMO.

Further, Weinstein et a1.98199made studies on thecomplexes of some tryptam ine co ngeners with imida-

zolium cation used as a m odel for secondary binding sitein the LSD /serotonin receptor, an d found tha t the in-teraction in the complexes was totally electrostatic innatu re; the transfer of charge to t he imidazolium cationwas negligible and the mutual polarization of themolecule was the major component of the electroncharge red istribu tion. T he degree of polarization af-fected the stabilization ene rgy of th e complex and de-pended upon th e mutua l orientation of th e molecules.A hypothesis for the interaction of tryptamine con-geners with the L SD/sero tonin receptor resulted fromthes e findings: “th e difference between the affinity of5-H T and th at of any other congener is related to thediscrepancy between th e pr eferred electrostatic orien-

tation of 5- H T and th at of congene r in the field of th ereceptor.”99J00

On the basis of their findings as t o the electrostaticnat ure of complexes an d the relative con tribution ofpolarization, exchange repulsion, and “charge-transfer”term s to th e stab ilization energies, Weinstein et al.99also assumed th at the charge redistribution accompa-nying complex format ion would be main ly“intramo lecular” in character: the polarization witheach molecule will enhan ce the electrostatic interactionbu t the re will be little ”overlap” or actual transfer ofcharge.

However, the significance of general charge-transferphenomenon is reinforced by the existence of good

correlations between the ionization poten tials and th e



646 Chemical Reviews, 1983, Vol. 83 , No. 6 Gupta, Singh, and Bindal

RBR a nd log P (eq 20) shows very poor role of hydro-phobicity. Bu t Nichols et al.35 claimed t ha t a secondorder relationship in log P was greatly improved. Theseauthors then pointed ou t tha t serotonin receptors maypossess a specific hydrophobic site th at accom modatesthe p ara s ubs tituent provided it is less tha n 5-6 A inlength.34v35Green et al.lo7 lso proposed a specific hy-drophobic site approximately at this region of the ser-otonin receptor.

Th e importance of th e length of th e 4-substituent hasbeen a lso argued by Kie r and G l e n n ~ n ~ ~ho obtainedeq 24. T he pa rabo lic corre lation of activity with the 3xputerm which increases by one su bgrap h as the length ofthe 4- substituent increases led them to suggest tha t amaximum potency will be obtained with an interme-diate length of th e 4-sub stituent chain. Th is suggestionis fully consistent with the finding tha t in (4-X -sub-stituted-2,5-dimethoxyphenyl)isopropylamineshe op-timum activity is associated with an alkyl or halo groupat the 4-position that is probably limited in bulk ton-propyl or bromo.

Fu rther s upp ort for this aspect comes from eq 25 and26 which correlate other "in vitro" activity data with

steric factors. Although V , or C M R represents thetotalsum of V, or MR of all sub stituen ts in the phenylring, almost all the compou nds tha t were included inderiving eq 25 or 26 (Table VI) belong t o th e series of(4-X-substituted-2,5-dimethoxyphenyl)alkylamines(exce ption is only 15 which is otherwise equ ivalent t o4,5-(methy1enedioxy)-substitutednalogue) where thevariation occurs only a t the 4-position. Correlationswere l inear due to the fact that th e substi tution a t the4-position in the entire series (T able VI) was limitedin bulk only up to the bromo group.

If the assumption that the 4-position of phenyl-alkylamines corresponds to the 7-position of trypt-a m i n e ~ ' ~ ~ J ~ ~s really true, it removes all the dou bt of

th e significance of ir7n tryptam ines activity as shownby eq 35-40.

The serotonin uptake inhibition activity of trypt-amine s also appe ar to be influenced by steric bulk ofsubstituents in the phenyl ring as well as in the sidechain (eq 44 and 48). Th ey probably affect the con-formations of th e molecules th at a re required for in-teraction of compounds with two different receptorsites.72 However, what is the ex act natu re of drug-re-ceptor interaction in this case th at c anno t be fully ex-plained, as he hydrophobic parameter was found to besignificantly correlated only in one case and , as alreadymentioned, TO E is hardly any meaningful param eter.Bu t since hydrophobicity is found to be imp ortan t indetermining the ability of tryptamines to displacespecifically bound [3H]serotoninand [3H]LSD rom ratcerebral cortex membrane (eq 49 and 50), the onepossible reason fo r a good correlation not existing be-tween the serotonin uptake inhibition activity and logP in the other case (upper group, eq 42) may be t ha tonly one of th e two recepto r sites involved would pos-sess the hydrophobic c haracter.

Hydrophobic character of molecules or ster ic bulk ofthe subs ti tuents appear to be most impo rtant in theactivities of LSD analogues. Eq uatio n 63 obtained byDu nn an d B ederkag4 for a series of side-chain onlysub stitute d LSD analogues shows very well th e depe n-dence of antisero tonin ac tivity on log P. Further, this

equation also shows that if t he d ummy parameter D ha s

ability of some psycho tropic drugs to inhib it high af-finity LS D binding in rat brain homogenates (eq 51),an d of a few to displace specifically bound LS D fromthe sam e (eq 52). Th e huma n da ta on hallucinogenicactivity of a group of compounds that includes membersfrom a ll differe nt classes of hallucinogens were shownto be correlated w ith EHoMos significantly as shownby eq 53. EHoMowas obtained by a very crude method(Huckel approximation), but for a comparative study

on 7r-electron system s the impo rtance of th is m ethodcann ot be com pletely overlooked. Several authors havediscussed tha t in the field of relative aromatic reactivity,the Huckel method is as good as any refined me-thod.l"l

However, the correlations of total orbital energy(TOE) with serotonin-uptake inhibit ion activity oftryptamines (eq 41 and 43 or 45 and 47) or with hal-lucinogenic or antiseroto nin activity of LSD analogues(eq 54-56) hardly convey any m eaning, as no particularsignificance has been attach ed t o this qua ntum chem-ical param eter.

Th e other parameter th at appears to be importantfrom these QSAR studies in the activities of halluci-

nogens is the hydrophobic cha racter of molecules. T hecorrelation of hallucinogenic activity of phenylalkyl-amines with log P as shown by eq 8 had led Barfknechtet al. to suggest tha t while drug action ultimately maybe related to chemical or electronic factors, distributionand transport to the receptor may also be importan t indetermining the activity of ha lluc ino ger ~s.~ ~he sameconclusion was drawn by Domelsmith and Houk6Ot6lfrom eq 4. T he low value of co rrelation coefficient ( r )in eq 8 was attribu ted to the variability in biologicalda ta an d the use of calculated log P values for certaincompounds, nonetheless, it did not u ndermine th e roleof chemical or electronir effects in hallucinogenic po-tency of drugs.

Correlation of rabbit hyperthermia produced by apar ticula r series of pheny lalkylamines includ ing mostly(4-X-substituted-2,5-dimethoxyphenyl)isopropylamineswith hydrophobic parameter (eq 15 and 16) further ad dto the importance of hydrophobic natu re of hallucino-gens in their activity. The ir LSD-like effect in rat,however, was found to be influenced also by steric effectof 4-sub stituent. Th e steric effects of 4-subs tituent hasbeen well d iscu ssed by a few a ~ t h o r s . ~ ~ , ~ ~n any sub-stitution series, the 4-sub stituent has been found to beof unique imp ortance, and although eq 15-17 indicatethe co mbined effect of hyd rophobic natu re of all sub -sti tuents in the ring, 7r4 has been found to be mostsignificant.g7 Domelsmith e t al.97have recently con-cluded that there are two significant indicators ofhallucinogenic potency of phenylalkylamines: the hy-drophobic nature of 4-substi tuent and fo r moleculeswithout a hydrophobic 4-substituent, the first ionizationpotential. Th ey showed ir4and IP1significantly cor-related with hallucinogenic potency and rabbit hy-pertherm ia a s well.

T he correlation of in vitro activity da ta with log P andMR4 or 1, (eq 21 and 24) reaffirm the role of th e hy-drophobic nature of molecules and steric bulk of 4-sub stitu en t in the drug-receptor interaction of phen y-lalkylamines, although the MR4 is a crude m easure ofthe lat ter and I4 s vaguely define d. If one does no ttheoretically justify a third-order relationship as ex-

pressed by eq 23, the first-order correlation between log




a non-zero value, i.e., th e s ub stitu ent is cyclic, the ac-tivity would be lowered. A possible explanation for thiseffect given by Du nn a nd B ederka g4 s tha t a cyclicsubstituent brings ab out a conformational rigidity tha timpairs the receptor contact .

Th at the steric bulk of the subs ti tuent in the sidechain is detrime ntal to the ac tivity is shown by eq 57 ,58 ,61 , and 62 . Not only the antiserotonin activity butalso the hallucinogenic activity of LSD analogues is

found to be related to th e size of th e substituent in th eside chain (eq 58) an d neither of these activities appe arsto be significantly affected by the su bstitue nts in thephenyl ring (com pare eq 59 with 57 and 60 with 58 andfor deta ils see ref 93). However, the ste ric bulk of thesubs ti tuent in the side chain probably affects the ac-t ivit ies by altering the hydrophobic nature of themoiety, as we foun d th at log P of com pounds in TableXI11 is well correla ted with V, of their NR1R2 group(unpu blished). Bu t the activity (log term ) is shown tohave a p arabolic correlation with log P and only linearrelationship with the size of th e substituent. This is notha rd to explain. T he value of log P corresponding t othe o ptimum activity is calculated t o be equal to 2.90

which correspon ds to a greater size tha n th at of the-NHC5H11 group (see Tab le X III) , for which the cal-culated V, would be 0.955 X lo2A3, and no equationshowing linear correlation between the activity an d sizeof th e sub stituen t incorporates a molecule th at ha s itsNR IRz group bigger th an this.93

Th e steric effect in the an tiserotonin activity of L SDanalogues is also manifested by e q 64. This equationled Glennon and Kierg5 o suggest that a bigger sub-stitu en t in the side chain would lead to enha nced ac-tivity, bu t the p resence of a b ranche d chain, a cyclicstructure, a heteroatom, or an unsaturated bond in itwould dimin ish its effect. However, all such factors ofa su bsti tue nt will have almo st parallel effects on the

hydrophobicity of the molecule. Th us, ultimately itapp ears , although th e hallucinogenic activity could notbe shown to be directly related with log P , that hy-drophobicity of th e molecules is very imp or tan t in de-termining the activities of LSD analogues and thatthere would be a hydrophobic zone at the receptorwhich will accommodate the substituent of the sidechain. Th e hallucinogenic activity is shown to be re-lated with antiserotonin activity (eq 65). This supportsthe idea tha t hallucinogenic activity may be d ue to th eantiserotonin action of d rugs on the receptor.

Th e role of e lectronic factors in th e activities of L SDanalogues remains questionable. Kumb ar and SivaSankar91pg2 ailed in the ir att em pt to correlate theiractivity w ith EHoMor for that m atter with any otherelectronic par am ete r reflective of general or localizedcharge-transfer process. W ith this reference, it is verydifficult to explain how the degree of electron delo-calization will influence any activity as claimed by theseauth ors on the basis of their eq 54-56. Two other ac-tivities of LSD analogues-toxicity and pyrogenesis-

were fou nd to be related w ith V, only (eq 66 and 67)and not with an y electronic parameter even with TOE.

Chemical Reviews, 1983, Vol. 83 , No. 6 64 7

the "in vitro" da ta are not com pletely free from errors,certain anomalies, discrepancies, and deviations oc-curring in the c orrelations may be excused, and it maybe therefore concluded from the discussions in thepreceding section tha t, a t the molecular level, electronic,hydropho bic, and steric factors play a do mina nt role invarious biological and p harm acolog ical actions of hal-lucinogenic drugs. Correlations of activities with to-pological parameter such as x accounted som etimes for

steric effects, otherwise they have been more of p re-dictive value than providing any und erstanding to th emechanism of drug-receptor in teraction. However,while hydrophobicity and steric factors appear to beimportant in all types of hallucinogenic drugs, theelectronic properties do not ap pear to be so imp ortan tin the case of indolealkylamines and LSD analogues asin the case of phenylalkylamines. W ith this back-ground, it is difficult to assume th at all types of hallu-cinogens have exactly identical mode of actions. Rather,the finding tha t ther e can be two receptor si tes forhallucinogens indicates that structurally and confor-mationally different m olecules will interac t with dif-ferent receptor sites and th at the binding a t one si te

might involve totally electronic interaction a nd a t theother totally hydrophobic. Because of the use of non-human experimental animals in most biochemicalstudies and in the correlations the biological data th atdo no t necessarily reflect the efficacy of t he d rug on itsbiological receptor bu t are a com posite of m any even tsincluding various stages of drug tra nsp ort, uptake me-taboism, an d excretion, it is difficult to say what is theexact mec hanism of actions of hallucinogens at the re-ceptor level. Because of thes e shortcomings QSARstudies should not be heavily relied upon . However, thedistribution of hallucinogens in the intact body, thelocalization in spe cific organs or in specific sites of o r-gans, the attempt to show agonistic or antagonistic

action w ith specific regard to thes e neu rotransm itters,the efforts to dem ons trate degrees of cross-tolerancebetween one another, etc., also have not been uniformlyso successful45 ha t a unified theo ry of mechanisms canbe drawn. Therefore, theory and ex perim ent both havea long way to go to provide an unquestionable theoryfor the m echa nism, mode, and site of actions of hallu-cinogens.

Acknowledgments. We are thankful to Mr. S. B.Bhise of the Pharmacy Depa rtment for fruitful dis-cussions and we gratefully acknowledge the financialassistance provided by U.G.C., New D elhi, Ind ia, forthis work.

VI. Conclusions

Since the subjective nature of hallucinogenic activity

in man leads to 2Ck25% error in the measu reme nP and

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