Indian Journal of Chemistry Vol. 40B, February 200 1 , pp. 129- 1 35

Comparative QSAR studies with molecular negentropy, molecular connectivity, STIMS and TAU indices : Part II--General anaesthetic activity of aliphatic

hydrocarbons, halocarbons and ethers t

Kunal Roy*t, Dipak Kumar Pal#, A U De# & Chandan a Sengupta#

Division of Pharmaceutical Chemistry, Seemanta Institute of Pharmaceutical Sciences, Jharpokharia, Mayurbhanj 757 086, Orissa, India

#QSAR Lab, Division of Medicinal & Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Calcutta 700 032, India

Received 5 November 1 999; accepted (revised) 24 March 2000

General anaesthetic activity of two sets of compounds, one (set A) comprising twenty seven aliphatic ethers and the other (set B) consisting of twenty one heterofunctional compounds (aliphatic hydrocarbons, halocarbons and ethers) is subjected to quantitative structure activity relationship studies with various topological indices and the relations are compared with atopological index Nv (vertex count). The relations of the activity of set A compounds with molecular connectivity index 'Xv (EV 83.4%), TAU (EV 79.7 - 83.9%) and STIMS (EV 77.3 - 84.8%) indices are comparable to that of Nv (EV 80.8%) while molecular negentropy I (EV 72.8%) showed somewhat inferior relation. In case of set B, Nv and I did not produce statistically acceptable relations while TAU indices explained 66.9-85.6% variation in the activity. The study reveals that the activity increases with the increase in Nv (molecular bulk) and functionality F (in case of set B) and decreases as the branchedness increases. Important contributions of branchedness, shape factors (STIMS like NX, NY and NB) and functionality F (in set B) towards the activity suggest that the non-specific nature of general anaesthetic action requires further evaluation.

General anaesthetics are depressant drugs that produce reversible loss of all sensation, which may be accompanied by unconsciousness. The other cardinal features of general anaesthesia i nclude muscle relaxation and abolition of reflexes. A myriad of molecular species are capable of producing anaesthesia. Despite vast amount of research and speculations concerning the mode of action of anaesthetic agents since the development of clinical anaesthesia, the exact mechanism is not known I . The action of volatile anaesthetics is considered structurally non-specific, i .e . , the biologic effects of these compounds are more closely correlated with their physical properties than with their chemical structures2• These compounds i nteract with the receptive tissue over a major portion of its surface rather than at selected regions and mere presence of structurally diverse compounds i n the tissues can lead to changes in solvent properties, volume or degree of disorder of structUle of membrane which i n turn produce depressant action. The forces of interaction

tPart J : Illdiall J Chelll, 38B, 1999, 664. + Address for correspondence : C/o Dr. A. G. Saha, Flat No. 2E, 8, Dr. Ashutosh Sastry Road. Calcutta 700 0 10 e-mail : Kunalroy-in @ yahoo.com

are l ikely to diffuse throughout the entire receptive site i nstead of being concentrated at one or two foci and the forces are thought to be long range forces, van der Waals or dispersion interactions3.

Many theories of anaesthetic actions are based on physico-chemical properties of the anaesthetic agents4. These i nclude lipid theory of Mayer and Overton ( 1 90 1 ), vapour pressure theory of Ferguson ( 1 939), size of anaesthetic agents (Mullins, 1 954), clathrate formation theory (Pauling, 1 96 1 ) etc. I t is generally accepted that these agents exert their effects by i nhibiting transmission i n the central nervous system (CNS) through non-specific interaction with synaptic membrane and I or associated proteins. The membrane perturbation theory (Trudell, 1 977; Ecanow, 1 979) suggests that these agents expand the membrane by fluidizing, or by disordering, the phospholipid bilayer and thus directly preventing normal ionic conductance.

Current theories 1 .5,6 implicate the hydrophobic regions of membrane proteins (or the protei n - lipid interface) as the site of action. Anaesthetics exert their effect by binding to hydrophobic pockets or clefts of membrane proteins (rather than by disturbing the lipid bilayer matrix), thus producing changes i n protein

1 30 INDIAN J CHEM, SEC B, FEBRUARY 2001

conformation altering receptor or channel function. Ligand gated ion channels appear to play a critical role in anaesthesia. Volatile agents potentiate the action of y-aminobutyric acid, the principal inhibitory neurotransmitter in the CNS. Inhibition of G-proteins and their related intracel lular second messengers may also be associated with the impaired signal transduction during anaesthesia. Further research is going on to provide new insight into the mechanism of general anaesthetic agents.

In view of the above, the present communication is an attempt to correlate general anaesthetic activity of aliphatic hydrocarbons, halocarbons and ethers with some topological parameters to explore the possibi lity of existence of any sort of structural requirements of these compounds for the activity which has been erstwhile considered non-specific.

Materials and Methods General anaesthetic activity of two sets of

compounds, one (set A) comprising aliphatic ethers and the other (set B) consisting of aliphatic

hydrocarbons, halocarbons and ethers, were subjected to QSAR studies by multiple linear regressional (MLR) technique. The literature (observed) values of the activity of the compound sets A 7 and B

3 are l isted

in Tables I and II. The various indices considered were atopological parameter (ATP)8.9 : Nv (vertex count of hydrogen suppressed graph) ; molecular negentropy (MN) IO : I (based on the information theory of Shannon and Weaverl l ) ; molecular connectivity index (MCI) 12. 1 3 : IXV (first order valence X developed by Kier & Hall) ; STIMS indices8.9• 14: NI, NY, NX, NB, NP and NS (denoting numbers of methylene-, tertiary-, quaternary-, branched-, terminal- and non-terminal vertices respectively in the hydrogen suppressed graph of the reference alkane) and TAU8. 1 5. 1 7 : T (first order composite topochemical index), T R (first order skeletal index of reference alkane), F (functionality index) and B (branchedness index). These indices have been discussed in detail in the Part I of the communication!). The original references were followed for the calculation of the

Table I-Observed and calculated general anaesthetic activity of compounds Set A (aliphatic ethers) SI . Compd No. Obs:

I Ethyl vinyl ether 2.82 2 Methyl iso-propyl ether 2.70 3 Diethyl ether 2.75 4 Methyl propyl ether 2.90 5 Ethyl cyclopropyl ether 3. 1 0 6 Ethyl iso-propyl ether 3.00 7 Methyl tert-butyl ether 3.00 8 Methyl sec-butyl ether 3.04 9 Methyl iso-butyl ether 3.00 10 Ethyl propyl ether 3 . 1 0 I I Methyl butyl ether 3. 1 5 1 2 Di-iso-butyl ether 3. 1 5 1 3 Ethyl tert-butyl ether 3. 1 5 14 Ethyl sec-butyl ether 3.22 1 5 Ethyl iso-butyl ether 3.22 16 Methyl amyl ether 3.40 1 7 Dipropyl ether 3.40 1 8 Ethyl butyl ether 3.30 19 Ethyl tert-amyl ether 3.40 20 Ethyl iso-amyl ether 3.45 2 1 Ethyl amyl ether 3.45 22 Di-see-butyl ether 3.45 23 Di-iso-butyl ether 3.30 24 Methyl cyclopropyl ether 2.85 25 Dimethyl ether 1 .85 26 Methyl ethyl ether 2.22 27 Propyl iso-propyl ether 3.26 Obs. = Observed; Calc. = Calculated; Res. = Residual = Obs. -Calc. (a). Taken fron Ref. 7 (b). According to Eq. E 12 (c). According to Eq. E 14 *Compounds 23 and 25 behave as outliers in cases of Eqs E I 2 and E 14.

General Anaesthetic Activity Calc. b Res. b

2.76 0.06 2.66 0.04 2.76 -0.0 1 2.76 0. 14 3. 1 3 -0.03 2.93 0.07 2.83 0. 1 7 2.93 0. 1 1 2.93 0.07 3.03 0.07 3.03 0. 1 2 3. 1 0 0.05 3 . 1 0 0.05 3.20 0.02 3.20 0.Q2 3.30 0. 1 0 3.30 0. 1 0 3.30 0.00 3.37 0.03 3.47 -0.02 3.57 -0. 1 2 3.64 -0. 19 3.64* -0.34* 2.86 -0.01

2.2 1 * -0.36* 2.48 -0.26 3.20 0.06

Calc.c Res.c

2.77 0.05 2.64 0.06 2.77 -0.02 2.77 0. 13 3.06 0.04 2.92 0.08 2.84 0. 16 2.92 0. 12 2.92 0.08 3.05 0.05 3.05 0 . 10 3.06 0.09 3. 1 2 0.03 3 . 1 9 0.03 3. 1 9 0.03 3.33 0.07 3.33 0.07 3.33 -0.03 3.39 0.0 1 3.47 -0.02 3.60 -0. 15 3.6 1 -0. 16 3.6 1 * -0.3 1 * 2.79 0.06 2.22* -0.37* 2.50 -0.28 3 . 1 9 0.07

ROY et al. ANAESTHETIC ACTIVITY OF ALIPHATIC HYDROCARBONS, HALOCARBONS AND ETHERS 1 3 1

Table II--Observed and calci.llated general anaesthetic potency of compounds Set B (aliphatic hydrocarbons, halocarbons and ethers) SI. Compound No. Obs ."

I CF4 - 1 .24 2 C2F6 - 1 . 1 9 3 CH4 -0.66 4 C2H4 -0. 1 5 5 C2H6 -0. 1 1 6 C)Hg 0.05 7 C2H2 0. 1 5 8 CCIFz 0.40 9 CH)CH=CHz 0.40 1 0 (CH2h 0.80 I I CFCl) 0.82 1 2 CH)CI 0.85 1 3 CH)I 1 . 1 5 1 4 CH)CH2Cl 1 .40 1 5 CH)CH2Br 1 .40 1 6 CH)CH2OCH2CH) 1 .52 17 CH2Ch 1 .52 1 8 CH)CH2Clz 1 .59 1 9 CHCl) 2.08 20 CF)CHCIBr 2. 1 1 2 1 CHCI2CF2OCH) 2.66

Obs. = Observed; Calc. = Calculated; Res. = Residual = Obs.-Calc. (a) Taken fron Ref. 3 (b) According to Eq. G5 (c) According to Eq. G9 * Compound I behaves as an outlier in case of Eq G9.

parameters and the calculated indices are shown in Tables III and IV. In case of set B, two compounds appearing in the original reference were excluded in the present study in view of the fact that some of the indices discussed here were not applicable for those.

Though correlation of set A compounds with molecular negentrop/ and that of set B with molecular connectiviti were previously reported, this communication attempts to compare those with relations involving TAU and STIMS indices in view of the diagnostic feature of TAU and STIMS schemes that may give mechanistic interpretations of biological activity. Other topological schemes i ncluding MN and Mel are devoid of such features. TAU and STIMS schemes are unique in that these unravel specific contributions of functionality, branchedness, shape and size factors to biological activity. Thus, a comparison among the relations involving these indices may explore relative suitability of the schemes in describing the activity.

MLR analyses were done using a software program RRR98 developed by one of the authors 1 8 . Statistical quality of the equations 19 was judged by examining the pu: ameters l ike EV (explained variance), r or R (correlation coefficient), F (variance ratio) and SEE

General anaesthetic Potenc:i Calc.6 Res.6 Calc.c Res.c

-0.6 1 -0.63 -0.26* -0.98* -0.38 -0. 8 1 -0.92 -0.27 0.00 -0.66 -0.73 0.07 0.30 -0.45 0.04 -0. 1 9 0.00 -0. 1 1 -0.25 0 . 1 4 0.27 -0.22 0.23 -0. 1 8 0.33 -0. 1 8 0.08 0.07 -0.26 0.66 0.08 0.32 0.57 -0. 1 7 0.53 -0. 1 3 0.80 0.00 0.23 0.57 -0.09 0.9 1 0.25 0.57 1 .0 1 -0. 1 6 0.74 0. 1 1 1 .73 -0.58 1 .46 -0.3 1 0.98 0.42 0.93 0.47 1 .2 8 0. 1 2 1 .23 0. 1 7 1 .48 0.04 1 .86 -0.34 1 .69 -0. 1 7 1 .63 -0. 1 1 1 .36 0.23 1 .85 -0.26 1 .95 0. 1 3 2.42 -0.35 1 .82 0.29 1 .76 0.35 2.79 -0. 1 3 2.39 0.27

(standard error of estimate). Significance of the regression coefficients and constants (intercepts) was judged by 'I' test. In case that intercept of an equation was statistically insignificant and omission of the same did not affect the quality of the equation, exclusion of the i ntercept gave statistically more acceptable equation. A compound was considered as an outlier for a particular equation when the residual value (difference between the calculated and observed values) exceeded twice the value of SEE of the equation.

Results and Discussion

The relations of general anaesthetic activity of the compounds of sets A and B are presented in Tables V and VI respectively . Equations of statistically acceptable quality only are included in the l ists. The regression coefficients, and the constants (intercepts), if any, of the listed equations are significant at 95% level if not stated otherwise and their standard errors have been mentioned beneath the corresponding values. The variance ratios (F) are significant at 99.9% level.

In case of aliphatic ether data set (set A, Table V), the atopological parameter Nv itself could explain 80.8% of the variance (r = 0.903). The relation with

1 32 INDIAN J CHEM. SEC B. FEBRUARY 2001

Table III-Topological indices of compounds Set A (aliphatic ethers) Sl. Compound ATP STIMS" MN MCI TAU No. (Nv) NI NY NX ( I) (:() T TRb F B

I Ethyl vinyl ether 5 3 0 0 1 1 .846 1 .640 0.246 2.4 1 4 2 . 1 69 0.000 2 Methyl iso-propyl ether 5 I I 0 1 0.939 1 .799 0.244 2.270 2.026 0. 144 3 Diethyl ether 5 3 0 0 9.360 1 .992 0.598 2.4 1 4 1 .8 1 7 0.000 4 Methyl propyl ether 5 3 0 0 13 .575 1 .904 0.222 2.4 1 4 2. 1 93 0.000 5 Ethyl cyclopropyl ether 6 4 I 0 1 4.222 2.548 1 .282 2.932 1 .650 0.068 6 Ethyl iso-propyl ether 6 2 I 0 1 5.29 1 2.386 1 . 1 20 2.770 1 .650 0. 144 7 Methyl tert-butyl ether 6 I 0 I 1 1 . 144 2. 1 1 2 0.634 2.56 1 1 .927 0.354 8 Methyl sec-butyl ether 6 2 I 0 17.699 2.337 0.782 2.808 2.026 0. 106 9 Methyl iso-butyl ether 6 2 I 0 1 5.29 1 2.260 0.577 2.770 2 . 1 93 0. 1 44 10 Ethyl propyl ether 6 4 0 0 1 7.926 2.492 1 .098 2.9 1 4 1 .8 17 0.000 I I Methyl butyl ether 6 4 0 0 1 7.926 2.404 0.722 2.9 1 4 2. 1 93 0.000 1 2 Di-iso-butyl ether 7 I 2 0 1 1 .204 2.78 1 1 .643 3. 1 26 1 .483 0.288 13 Ethyl tert-butyl ether 7 2 0 I 1 5 .7 1 4 2.700 1 .5 10 3.06 1 1 .55 1 0.354 14 Ethyl sec-butyl ether 7 3 I 0 22.268 2.924 1 .658 3.308 1 .650 0. 106 15 Ethyl iso-butyl ether 7 3 I 0 1 9.860 2.847 1 .454 3.270 1 .8 1 7 0. 144 1 6 Methyl amyl ether 7 5 0 0 22.496 2.904 1 .222 3.4 14 2. 1 93 0.000 17 Dipropyl ether 7 5 0 0 1 6.475 2.992 1 .598 3.4 14 1 .8 17 0.000 1 8 Ethyl butyl ether 7 5 0 0 22.496 2.992 1 .598 3.4 1 4 1 .8 1 7 0.000 19 Ethyl tert-amyl ether 8 3 0 I 23.787 3.26 1 2.07 1 3.62 1 1 .55 1 0.293 20 Ethyl iso-amyl ether 8 4 I 0 24.6 1 7 3.347 1 .954 3.770 1 .8 17 0. 144 2 1 Ethyl amyl ether 8 6 0 0 27.252 3.492 2.098 3.9 14 1 . 8 1 7 0.000 22 Di-see-butyl ether 9 3 2 0 23.89 1 3.857 2.7 19 4.202 1 .483 0.2 1 2 23 Di-iso-butyl ether 9 3 2 0 1 9.070 3.703 2.309 4. 1 26 1 . 8 1 7 0.288 24 Methyl cyclopropyl 5 3 I 0 10.040 1 .960 0.406 2.432 2.026 0.068

ether 25 Dimethyl ether 3 I 0 0 3.3 1 7 0.8 1 7 - 1 . 1 55 1 .4 1 4 2.569 0.000 26 Methyl ethyl ether 4 2 0 0 9.485 1 .404 -0.279 1 .9 1 4 2. 1 93 0.000 27 Propyl iso-propyl ether 7 3 0 1 9.860 2.886 1 .620 3.270 1 .650 0. 144

(a) Other STIMS indices : NP = Nv - (NI + NY + NX); NB = NY + NX; NS = Nv - NP (b) T R of TAU scheme is same as IX of MCI scheme in case of acycl ic compounds

Table IV-Topological indices of compoundss Set B (aliphatic hydrocarbons. halocarbons and ethers) Sl. Compd ATP STIMS" MN MCI TAU No. Nv NI NY NX (1) eXV) T TRb F B I CF4 5 0 0 I 1 .087 -0.756 - 1 .5 1 2 2.000 3.5 1 2 0.41 4 2 CZF6 8 0 0 2 2.556 -0.884 -2.0 1 8 3.250 5.268 0.664 3 CH4 I 0 0 0 1 .087 0.000 0.000 0.000 0.000 0.000 4 CZH4 2 0 0 0 2.26 1 0.500 0.200 1 .000 0.800 0.000 5 CZH6 2 0 0 0 2.556 1 .000 1 .000 1 .000 0.000 0.000 6 C}Hs 3 I 0 0 6. 1 84 1 .4 1 4 1 .4 14 1 . 4 14 0.000 0.000 7 CzHz 2 0 0 0 1 .204 0.333 0. 1 1 1 1 .000 0.889 0.000 8 CClF2 5 0 0 I 2.29 1 0.756 -2.446 2.000 4.446 0.4 1 4 9 CH}CH=CHz 3 1 0 0 6.555 0.986 0.59 1 1 .4 1 4 0.823 0.000 10 (CHzh 3 3 0 0 2.488 1 .500 1 .500 1 .500 0.000 0.000 1 1 CFCI.1 5 0 0 1 2.064 1 .5 1 2 -2.9 1 3 2.000 4.9 1 3 0.4 14 1 2 CH}CI 2 0 0 0 2.064 1 . 1 34 - 1 .690 1 .000 2.690 0.000 1 3 CH}I 2 0 0 0 2.064 2.532 -3.627 1 .000 4.627 0.000 14 CH.1CHzCI 3 I 0 0 5. 1 9 1 1 .509 -0.488 1 .4 1 4 1 .902 0.000 15 CHJCH2Br 3 I 0 0 5 . 1 9 1 2.097 - 1 .293 1 .4 1 4 2.707 0.000 1 6 CH.1CHzOCHzCH) 5 3 0 0 9.360 1 .992 0.598 2.4 14 1 .8 1 7 0.000 17 CHzClz 3 I 0 0 2.29 1 1 .603 -2.39 1 1 .4 1 4 3.805 0.000 18 CHJCHzClz 4 0 0 5. 1 9 1 1 . 887 - 1 .374 1 .732 3. 1 07 0. 1 82 19 CHC1} 4 0 0 2.064 1 .964 -2.928 1 .732 4.660 0. 1 82 20 CF}CHCIBr 7 0 1 5.793 1 .5 1 1 -3.454 2.943 6.398 0.47 1 2 1 CHClzCFzOCH} 8 1 0.3 1 5 1 .832 -3.285 3.504 6.789 0.4 10 a ) Olher STIMS indices : NP = Nv - (NI + NY + NX); NB = NY + NX; NS = Nv - NP (b) T R of TAU scheme is same as IX of MCI scheme in case of ac�C\ic comEollnds

ROY et al. ANAESTHETIC ACTIVITY OF ALIPHATIC HYDROCARBONS, HALOCARBONS AND ETHERS 1 3 3

Table V-Relations o f general anaesthetic activity o f compounds Set A (aliphatic ethers) with various indices Model equation Log lie = L {3jXj + a, 11 = 27; YIII,all = 3.060; cry = 0.371

Eqn Type of Regression coefficient(s) and constantt Statistics No. index 1:31 1:32 1:33 ex EV%

(s.e.) (s.e.) (s.e.) (s.e.) (r or R)

E I ATP 0.236 Nv + 1 .558 80.8 0.022 0. 147 (0.903)

E2 MN 0.055 I +2. 1 50 72.8 0.007 0. 1 15 (0.859)

E3 MCI 0.478 lX' + 1 .845 83.4 0.042 0. 1 10 (0.9 17)

E4 TAU 0.393 T +2.625 82.0 0.036 0.050 (0.909)

E5 TAU 0.5 1 8 TR + 1 .508 83.9 0.044 0. 1 36 (0.920)

E6 TAU 0.259 Nv -0.570 B* * +1 .476 82.8 0.024 0.287 0. 145 (0.9 17)

E7 TAU 0.268 NS + 1 .201 B + 1 .932 8 1 .7 0.026 0.262 0. 1 08 (0.9 1 2)

E8 TAU 0.277 NI +2.470 B + 1 .954 79.7 0.029 0.3 19 0. 1 13 (0.902)

E9 TAU 0.280 NI +0. 143 NP* + 1 .5 1 5 B + 1 .672 82.0 0.027 0.07 1 0.566 0.222 (0.9 1 8)

E I O TAU 0.28 1 NI +0. 1 1 5 NY +2. 1 79 B + 1 .906 82.9 0.026 0.049 0.3 19 0.098 (0.92 1 )

E l l TAU 0.279 NI +0. 167 NB +1 .725 B + 1 .9 1 4 82.4 0.027 0.078 0.458 0. 1 1 5 (0.9 19)

E I 2 STIMS 0.27 1 NS +0. 170 NP + 1 .601 84.8 0.024 0.03 1 0. 1 3 1 (0.927)

E I3 STIMS 0.267 NI +0.382 NY +0.693 NX + 1 .956 79. 1 0.Q28 0.055 0. 1 1 9 0. 1 00 (0.903)

EI4 STIMS 0.277 NI +0.202 NP +0.2 17 NB + 1 .537 84.7 0.025 0.045 0.061 0. 1 27 - (0.930)

E I 5 STIMS 0.263 NI +0.305 NP +1 .458 77.3 0.030 0.043 0. 1 77 (0.889)

E I6 STIMS 0.270 NI +0.267 NP +0. 1 29 NY + 1 .462 8 1 .6 0.027 0.041 0.050 0. 1 34 (0.9 15)

EI7 STIMS 0.266 Nv -0. 1 2 1 NB + 1 .452 83.7 0.024 0.052 0. 142 (0.92 1 )

E l 8 STIMS 0.255 Nv -0.092 NY* + 1 .488 82.6 0.024 0.048 0. 144 (0.9 16)

n = No. of data points; Y meun and CJy are arithmetic mean and standard deviation respectively of the response variable (activity). # t values of the regression coefficients and constants are significant at 95% level l df = n - nv - i ; nv = no. of

predictor variables; i = I if intercept is present; i = 0, otherwise] * Significant at 90% level V F values are significant at 99.9% level; df = (nv, n - nv - i).

SEE (Fv)

0. 163 ( 1 1 0. 1 ) 0. 193 (70.5) 0. 1 5 1

( 1 3 1 .5) 0. 1 57

( 1 19.2) 0. 149

( 1 36.9) 0. 154 (63.5) 0. 159 (59.0) 0. 1 67 (52. 1 ) 0. 1 57 (40.4) 0. 1 53 (43.0) 0. 1 56 (4 1 .5) 0. 145 (73.3) 0. 170 (33.7) 0. 145 (49. 1 ) 0. 176 (45.3) 0. 1 59 (39.4) 0. 150 (67.6) 0. 155 (62.6)

MN was inferior to this (EV = 72.8%, r = 0.859) while in cases of Mel (EV = 83 .4%, r = 0.9 1 7) and TAU (EV = 79.7 - 83 .9%, r = 0.902 - 0.920), the relations improved further, though marginally. The best two relations obtained were with STIMS indices (Eqs E I 2 and E 1 4) explaining 84.7 and 84.8% of the variance. The observed activi ty values of aliphatic

ethers 7 and corresponding calculated values according to the equations E I 2 and E 1 4 are shown in Table I.

From Eqn E6 it is evident that the act ivity i ncreases with the rise i n vertex count Nv (molecular bulk) and decreases as the branched ness (B) increases. Effects of Nv and branched ness ( in terms of NB and NY) are also evinced from equations E 1 7 and E 1 8 . However,

1 34 INDIAN J CHEM, SEC B , FEBRUARY 2001

Table VI-Relations of general anaesthetic potency of compounds Set B (aliphatic hydrocarbons, halocarbons and ethers) with various indices

Model equation Log lip = L (3jXj + ex, 11 = 2 1 ; YtIl"lII = 0. 740; Uv = 1 . 061

Eqn Type Regression coefficient(s) and constant# Statistics No. of � I �2 �3 �4 ex.

(s.e). EVO/O SEE

index (s.e.) (s.e). (s.e). (s.e). (r or R) (Fv)

G I MCI 1 . 0 10 IX" 0. 137

G2 TAU 0.446 Nv -7.679 B +0.483 F 0. 140 1 .276 0.094

G3 TAU 1 .343 NY -4.506 B +0.4 14 F 0.342 0.795 0.065

G4 TAU 0.335 NS -4.833 B +0.44 I F 0. 133 0.936 0.077

G5 TAU 0.265 N I + 1 .87 1 NB -9. 174 B 0. 105 0.443 1 .4 17

G6 TAU 1 .8 14 NB -9.588 B +0.434 F 0.503 1 .602 0.066

G7 TAU 1 .463 NY -0.703 NP +0.450 F 0.399 0. 160 0. 1 1 5

G8 TAU - 1 .703 NX +0.484 F 0.307 0.057

G9 TAU 0.480 Nv -2.748 NX +0.369 F 0.096 0.290 0.064

vide foot Ilotes of Table V

the positive regression coefficients of B , N B, NY and NX in the equations E7 through E 1 6 should not be misinterpreted. The term Nv being absent, the impact of branchedness on the activity for the compounds having same vertex count is not perceptible from these equat ions. It may be explained taking the example of Eqn E8. For a given value of NI, any increase in branched ness (B) will automatically mean increase in Nv which has positive i mpact on the activi ty thus masking the effect of B (which has negative i mpact). The equations E7 through E l 6 may be used to predict the activities of al iphatic ethers having various skeletal features.

In case of data set B (Table VI), the atopological parameter, Nv , and molecular negentropy, I, did not give statistically acceptable equations. Mel could explain 72.6% variation in the activity (r = 0.860) while explained variance in case of TAU was in the range 66.9 - 85.6% (r = 0.830 - 0.937). The compounds of set B being heterofunctional, STIMS indices, which have no provision to indicate functionality at the present stage, were not sufficient to explain the variation in the activ i ty. From the equation G2 i t is evident that the activity increases as the values of Nv and F increase while the same decreases with the increase in branchedness (B) . A simi lar pattern of relation i s found in Eqn G9 where the regression coefficients of Nv and F have posi t ive

+0.375 F 0.063

-0.436 0.201 - 1 . 167 0.5 1 2

+ 1 . 1 03* 0.563

- 1 .2 1 1 0.345

72.6 (0.860)

7 1 .0 (0.868)

76.0 (0.885)

66.9 (0.838)

80.0 (0.9 1 1 )

74. 1 (0.875)

68.2 (0.854)

67.4 (0.83 1 )

85.6 (0.937)

0.556 (54.0) 0.572 ( 1 7.3) 0.521 (35.9) 0.6 1 1 (24.4) 0.475 (33.5) 0.54 1 (32.8) 0.598 ( 1 5.3) 0.606 (36.9) 0.403 (40.6)

values while the term NX possesses a negative coefficient. However, the pOSItIve regression coefficients of NB in equations G5 and G6 and that of NY in Eqn G7 should not create any confusion regarding the i mpact of branchedness; the clarifications already given for a s imilar case in Set A compounds apply here also. That the functionali ty index F contributes significantly to the activity i s evident from equations G2 through G9. Activity of aliphatic hydrocarbons, halocarbons and ethers of different skeletal features may also be predicted from these equations. Listed in Table II are the calculated values of anaesthetic potency of set B compounds according to the equations G5 and G9.

The above QSAR study reveals that increase in molecular bulk and decrease in branchedness are conduci ve to the act iv i ty, i .e. , large flat molecules capable of dispersi on interactions over an extended portion of receptive t issue are preferred for the aC1ivity. The significant contribution of the shape factors l ike NX, NY and NB implicates the i mportance of molecular shape and total surface area. In case of set B compounds, the functional i ty index F was a significant contributor while in case of set A compounds it was not · so because only homofunctional ethers "vere considered in the l a t ter.

Importance of branchedness, shape factors (NX , NY, NB) and functional i ty (in set B) suggests that

ROY et al. ANAESTHETIC ACTIVITY OF ALIPHATIC HYDROCARBONS, HALOCARBONS AND ETHERS 1 35

interactions of the compounds with the critical reaction site may not be totally non-specific as considered generally. The events l ike passage through membranes or attainment of sufficient concentration at the reaction site etc. , which precede the interaction phenomenon, may be governed by various physico-chemical parameters making these processes non-specific, but some structural features of the compounds appear to be important during the interaction with the receptive site. Kier and Hall) also questioned structural non­specificity of drug action at the molecular level . They suggested that some definitive characters in the structure l ike appreciable aromatic surface area or alkyl chain or electron-richness etc. may be contributing factor during interactions, and structurally diverse compounds also may possess some sort of structural commonality qual ifying them for a specific activity which is otherwise considered non-specific. Hence, non-specific nature of general anaesthetic activity requires further introspection.

Acknowledgement The authors thank Prof. K D Chowdhury, Principal ,

SIPS, Orissa for providing necessary computational facil ities to one of the authors (KR).

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