QSAR of adenosine receptor antagonists I : Exploration of...
Transcript of QSAR of adenosine receptor antagonists I : Exploration of...
Indian Journal of Chemistry Vol. 428 , June 2003, pp. 1485-1496
QSAR of adenosine receptor antagonists I : Exploration of receptor interaction sites of 1 ,2-dihydro-2-phenyl-I ,2,4-triazolo[ 4,3-a]quinoxalin-I-one derivatives
using AMI calculations
Kun a l Roy
Drug Thcoretics and Chcminform3t ics Lab. Division of Medicinal and Pharmaccutical Chemistry. Department or Pharmaceutical Tcchnology. Jadavpur Uni versity, Kolkat<l 700 032. India
Email : kunalroy_in @yahoo.com
URL : hllp ://www.geoci ties.com/kunalroy_in
Received 5 August 2002; accepted (revised) 24 December 2002
QSAR of adenosine reccptor antagonist I ,2-dihydro-2-phenyl- 1 ,2,4-tri azoloI4,J-a lquinoxalin- I-one deri vat i ves has becn attempted to explore using AM J calculations with an objective to identify different interacti on sites on the ligands for different receptor sUbtypes [A I> A2A and A)J. Five possible interaction sites have been suggested and it is observed that the requirements fo r optimum binding for these receptor sUbtypes (AI> A2A and A)) are different to some ex tent.
Adenosine is an endogenous nucleoside that modulates a wide variety of physiological effects through activation of G-protein coupled AI, A2A, A2B and A3 receptors 1.2. Presence of the receptors on basically every cell s makes them an interesting target fo r the pharmacological intervention in many pathophysiological conditions2. The sy nthesis of agonists and antagoni sts to the adenosine receptors and their cloning has enabled the exploration of their physiological function s.
Adenosine shows general inhibitory effect on neuronal acti viti, which is med iated by AI receptors4
.
However, excitatory actions of adenosine, medi ated by acti vation of A2A receptors, have also been demonstrated5
. Evidences suggest the ro le of adenosi ne in a diverse array of neural phenomena including regulation of sleep and the level of arousal, neuroprotection, regul ation of seizure susceptibility, locomotor effects, analgesia. mediat ion of effects of ethanol etc4
. The somnogenic action of adenosine in the basal fo rebrain is mediated by AI receptors and its expression might be regulated by induction in the nuclear factor kappaS protein as its tran cription factor6
. Increase of adenosinergic neuromodul ation may be one of the several future therapeuti c strategies in neuroprotection] Selective agoni sts of adenos ine AI receptor are shown to have neuroprotective ac ti on in brain ischemi a6
.s, while A2A receptor antagoni sts (like KW-6002)
are being developed for treatment of neurodegenera-
ti ve diseases like parkinsoni sm9.lo. AI receptor medi
ated mechani sm for protection against myocardi al stunning is under investigation II . AI receptor antagonists may provide a therapeutic tool to prevent contrast-media induced acute renal failure in patients with diabetes mellitus l2.
The A2A receptors are thought to playa ro le in a number of physiological and pathological conditions. A2A receptors show antagoni sti stic interac tions with d . (D ) 13 14 A . opamlI1e 2 receptors '. 2A receptor agonl sts may be useful for treatment of certain type of seizures or sleep disorders 13. A2A receptor has become a focus of major interest in the treatment of inflammatory renal injury because of its ability to broadly inacti vate inflammatory cascade.
Only recently, A2B receptors have been implicated in the regul ation of vascular smooth muscle tone, cell growth, intestinal function and neurosecreti on. The ro le of A2B receptors in mas t cell acti vati on makes it a
I h . . h 15 nove t erapeutlc target In ast ma · . Acti vati on of A3 receptors has been shown to
stimulate phosphilipase C and 0 and inhibit adenylate cyclase. It also causes release of infl ammatory mediators like hi stamine from mast ce ll s. A3 receptors play important role in brain ischemia, immunosuppression and bronchospasm. Selective A3 agoni sts andlor antagoni sts have been indicated as potenti al drugs for the treatment of asthma and infl ammation while selecti ve agonists have been shown to have card ioprotec
1486 INDIAN J. CHEM., SEC B, JUNE 2003
live action l. A} receptors playa key role in the inhibitory and stimulatory growth activities of adenosine. A3 receptor agonists possess dual activity: antiproliferative activity towards tumor cells and stimulatory effect on bone marrow cell s. Activation of A3 receptors may serve as a new approach for cancer therapyl6
Accumulated evidences indicate a widening role of adenosine receptors in many therapeutic areas like immunological and inflammatory responses, respiratory regulation, renal protection, parkinsonism, car-:I . . t'f I ry 16· 18 I I I ( loprotectl ve e ects, cancer etc .-. . n t 1e ast two decades, many efforts have been made to develop selective adenosine receptor ligands for their potential
. . 9 70 therapeutic uses '- . In this present effort, QSAR of adenosine receptor
antagonist 1 ,2-dihydro-2-phenyl-l ,2,4-triazolo[ 4.3-a]qui noxalin-l-one deri vati ves, recently reported by Colotta et 01.
21, has been attempted to explore using
AMI calculations with an objective to identify different in teraction sites on the li gands for different receptor subtypes [AI , A2A and A3]. The biological data consist of the binding affinity of the compounds at bov ine A I and A2A and human cloned A, receptors (there is species difference in A3 primary amino acid sequence while for AI and A2A adenosine receptor subtypes there is a good amino acid sequence homolog/I).
Materials and Methods The biological activity values and structural fea
tures of the compounds are presented in Table I. Compounds without quantitative biological activity data in a particular se ries (All A2P..! A,) were exc luded from the study . One compound appearing in the original data set was not included in the present study because of absence of the oxo subst ituent in the triazole ring, a feature that is present in all other compounds. Quantum mechanical calculations were done according to AM I (A ustin Model 1)22-24 method using Chem 3D Pr025 package. The general structure of the compounds (Figure 1) was drawn in Chel1l Draw Ultro lIe r 5.025 and it was saved as the templ ate struct ure. For every compound, the template structure was suitably changed considering its structural features, copied to Chell1 3D ver 5.025 to create the 3-D model and finally the model was 'c leaned up'. The nonhydrogen common atoms of the compounds were given a serial number so that these maintain same serials in all the models (Figure 1). Next, energy minimizati on was done under MOPAC module usi ng RHF
A
, , '- ___ __ __ _ _______ _____ .J
E
Figure li - General struclure of 1,2-dihydro-2-phcnyl-I .2,4-Iri azoloI4,3-a]quinoxalin-l -one derivatives: the common atoms have been numbered I through 20 ( it has no re lat ion to the chemical nomenclature . ystcm) and important intcraction site~ A through E have been suggested.
(restricted Hartree-Fock : closed shell) wave function. The energy minimized geometry was used for calculation of Wang-Ford charges (obtained from molecular electrostatic potential surface) of different atoms.
The charges (qx) of different atoms (x) were subjected to intercorrelation study. The biological activity data of the compounds [pK().1M)] were subjected to regression with the charges of di fferent common atoms and also their26 different combinations to obtain the best relat ions using the program A UTOREC27 developed by the author. Some indica tor variables, which emerged as important descriptors from the preliminary analyses, were retained du ri ng finding out the best rel ati ons involving differem combinations of charge parameters in some cases (vide infra ). For the relations havin g more than one predictor variables. only those variables with less intercorrelation were cons idered (a cutoff intercorrelation val ue of 0.7 was considered only as a screening process) . Further, relations having correlation coefficients higher than those of the best equations involving less number of predictor variables were only recorded.
The regression analyses were carried out using a GW-BASIC program RRR9827
. The stati stical quality of the eq uati ons28 was judged by the parameters like explained variance (R}, i.e., adjusted R 2), correlation coefficiel1l (r or R), standard error of estimate (s), average of absolute values of the residuals (A VRES), variance ratio (F) at specified degree of f reedom (df) and 't' values of the regression coefficienrs. Use of more than one variable in a multi variate eq uati on was justified by intercorrelation study. All the accepted
ROY : QSAR OF ADENOSINE RECEPTOR ANTAGONISTS I 1487
Table ( - Adenos ine receptor binding acti vity of I ,2-dihydro-2- phenyl- 1 ,2.4-triazolo[4,3a Jquinoxali n- l -ones
Compd R R/X
2
3
4
5
6
7
8
9
10
1\
12
13
14
15
16
17
18
19
20
21
22
23 24
25
26
27
28
29
30
3 1
32 33
34
35
36
*nM
H
H
H
3-CHJ
4-CH3
3-F
4-OCH3
4-CI
H
3-CH,
3-F
4-CI
H
3-CH3
3-F
H
H
H
H
H
H
H
H
H
H
H
3-CH,
H NHBn
H NH,
H H
H H
H H
H H
H H
H H
cyclo-hexyl H
cyclo-hexyl H
cyclo-hexyl H
cyclo-hexyl H
cyclo-pentyl H
cyclo-pentyl H
cyclo-pentyl H
CH,Ph H
(CH,),Ph H
(CH,hPh H
CH,CH(Ph), H
COCH3 H
COCH2CHJ H
CO Ph H
COCH, Ph H
CONHPh H
CONHC6H..-4- H OCH3 H H
H H
4-CH, H H
H
H
H
H
H
H
H
H
3-F H
4-OCH, H
4-CI H
H CH,
4-CH, CH3 4-CI CH3 H n-CJH7
H CH,C::CH
Bn = Benzyl, pK = - log[K(~M)]
1 - 26
Binding affinity for different receptor subtypes Bov ine A, Bovine A2A Human A3
K;* pKAI Calc Res K;* pKA2A Calc Res K;* pKA3 Calc Res
730
9.2
11.0
20.0
19.5
28.5
312.0
426.0
1.43
4.2
4.9
80. 1
0.42
1.2 1
1.1
55.0
4.8
17.9
4.3
9.3
89.6
6.3
0. 137 0.473 -0.336
2.036 1.606 0.430
1.959 1.3 16 0.643
1.699
1.71 0
1.545
0 .506
0.37 1
1.353 0.346
1.652 0.058
1.850 - 0 .305
1.2 19 -0.7 13
0.299 -0.072
6.5
18.7
49.0
14.6
85.8
72.0
376.0
2 .187
1.728
1.31 0
1.836
1.067
1.1 43
0 .425
2.074 0 .11 3
1.806 -0.078
0.794 0.51 6
1.222 0.6 14
0.870 0.197
1.784 -0.641
0.447 -0.022
2.845 2.46 1 0.384 1370.0 -0. 137 -0. 177 0.040
2.377 2.694 - 0.3 17
2.3 10 3.0 13 -0.703
1.096 1.874 -0.778
3.377 2.440 0.937
2.9 17 2.486 0.43 1
2.959 2.9 13 0.046
1.260 1.267 -0.007
2.3 19 1.557 0.762
1.747 1. 809 -0.062
2.367 2.040 0.327
66.0 1.1 8 0.742 0 .438
986.0 0.006 -0.136 0. 142
1400.0 -0. 146 0.238 -0.384
148.0 0 .830 0 .798 0.032
2.032 2.4 12 - 0.380 28 18.0 -0.450 -0.695 0.245
1.048 1.475 -0.427
2.20 1 2. 147 0.054
54.0 1.268 0.89 1 0.377
28.5
48.3
157.0
45.3
329
1.545
1.3 16
0.804
1.344
0.483
506 0.296
548 0.26 1
44.2
56. 1
55.4
1.355
1.25 1
1.256
27.5 1.56 1
173 0.762
1700.0 -0.230
1.226 0.319
1.274 0.042
1.130 -0.326
1.226 0.1 18
1.058 -0.575
1.1 78 0. 177
1.1 06 0.145
1.226 0.030
1.250 0.3 11
1.154 -0.392
20 1.0 0.697 1.1 54 -0.457
40.9 1.388 1.1 78 0.2 10
1020.0 -0.009
2.0 2.699 2.482 0.2 17
15.8 1.80 I 2.434 -0.633
1.47 2.833 2.458 0.375
3.75 2.426 2.386 0.040
50.8 1.294 1.1 52 0 .1 42 2300.0 -0.362 0 .437 -0.799 276.0 0.559 1.034 - 0.475
0.0 18 0.747 -0.729 2600.0 -0.4 15 0.776 - 1.1 9 1 2800.0 -0.447 -0.034 -0.4 13 960.0
5 15 .0
436.0
0.288 0.40 I -0.1 13
0.36 1 0.275 0.086
155.0 0.8 10 0 .5 11 0.299
200.0 0.699 0 .905 - 0.206
934.0 0 .03 0.200 -0. 170
10 15.0 -0.006 -0.236 0.230
309.0 0 .510 0.20 I 0 .309
406.0 0.39 1 0 .090 0.30 I
2200.0 -0.342 0.058 -0.400
80.0
9 1.0
25.0
63.0
16.0
11 4.0
36.6
504.0
137.0
1.097 1.130 -0.033
1.04 1 1.1 78 -0. 137
1.602 1.202 0.400
1.20 I 1.058 0. 143
1.796 1.1 54 0.642
0.943 1.034 - 0.09 1
1.437 1.1 30 0.307
0.298 0.598. - 0.300
0.863 0.334 0.529
1246.0 -0.096 -0.3 13 0.21 7
479.0 0.320 0.766 -0.446
Calc = Calculated values; Res = Observed (pC I/pC, /pC.,) - Calculated Binding affiniti es (A/ A'A / A, ) have been calculated according to Eqs. 9/ 19/27.
1488 INDIAN J. CHEM .. SEC B. JUNE 2003
equations have regression constants and F ratios significant at 95 % and 99% levels respectively , if not stated otherwise. A compound was considered as outlier if residual is more than twice the standard error of estimate for a particular equation . In case that intercept of an equation was statistica lly insignificant and omission of the sa me did not affect the quality of the equation. exclusion of the intercept gave stati stically more acceptable equation.
Results and Discussion The charge parameters of different co ml1lon atoms
of the compounds are given in Table II . Stepwise development of QSAR equati ons is shown in Table III . Stati stical quality of the binding affinities with different combinations of charge parameters with or without indicator parameters is shown in Tables IVVI. The Discussion part uses arbitrary numbering assigned to the common atoms of the co mpounds (Figu"e 1), which has no relation to the chemi ca l nomenc la ture system. Energy minimized geometri es of the most active members in the indi vidual series [(a) : compound 13 (A I), (b) : compound 1 (A2A), (c): compound 22 (A ~ ) I are shown in Figure 2.
QSA R of A I receplOr binding qlfinity Table III shows that indicator va ri able I denoting
resence or absence of cyclopentylamino or cyclohex ylam ino group at RI positi on ca n exp lain 34.9% variance of the AI bindin g affinity (Eq. 1) whi ch is increased to 47.0% when another indicator variable 1m denoting presence or absence of - C H2CO group (as a part of alkylamino group) at RI position is used (Eq. 2) . These two predictor va ri ab les (I and Ico) were retained when the bi olog ica l act ivity was correlated with different combinati ons of charge parameters of different common atoms (Table IV). The atom 8 (Cs)
merged as sin gle best charge parameter (Eq. 3). The best equati ons with hi gher number of charge para me-
ters invo lved atoms C8 & C I9 (Eq. 4), CR, C I6 and C I9 (Eq. 5) and CR, N13• C I6 and C I9 CEq. 6). However, atoms C I6 and C I9 are considerabiy autocorrelated (Table VII) . Hence, a parameter q16+ 11J was defined as sum of charge parameters of atom C I6 and Cl l) and the resultant eq uation (Eq. 7) was statistically similar to Eq. 6. Replacement of the parameter q8 in Eq. 7 with q7 yields an equation (Eq. 8) with similar statistical quality. Atoms Cs and N7 are highly autocorrelated (Table VII) and the charge values are of opposite sign . A new parameter qS-7 was defined to denote diffe rence between the charge parameter va lues of atoms Cs and 7 and Eq. 9 was obtained. Remov ing poss ibl outliers (co mpounds 25, and 2S & 13). Equations 10 and II were obtained. The ca lculated binding affi nity va lues according to Eq. 9 are given in Table I. Autocorrelation among the important predictor vari ables is presented in Table VII.
From the results it appears tha t presence of cyclopentylamino or cyclohexylamino group at RI pos ition and a CH }CO fragment as a part of alkylami no substituent at RI is conducive to the adenosine AI receptor binding affinity. The atom N7 (nitrogen) with its adj acent (o rtho-) oxo or exocy li c amino substituent pl ays important rol e in the AI binding affinity. Futher. atom 13 (one of the triazo le nit rogens) also modul ate significantly the binding affinity. The atoms CI6 and CI9 signify the importance of the benzene ring and substituents on it.
QSAR of AlA reap/or hinding (!/Ji ni')' From Tables III and V it is ev ident that charge pa
rameter of atom N IJ emerged as si ngle best parameter CEq . 12) for A2A receptor binding affinit y. The best bivariate relati ons in volved atoms NIJ & C I and IJ & C2 while the best tri va ri ate relation invo lved atoms CI, NI2 and C I6 (the qu ality of the tri variate re lations involving charge parameters of atoms CI, NIJ & CI7 and C2• NI 2 & C I6 and C2, NIJ & C 17 closely foll ow that or
Figure 2 - Encrgy min illli zcd gco lllc iri c, o f the most ac ti vc Illcmbcrs in the indIv idual seri es I (a) : co mpound 13 (AI), (b) : cOlllpolind I I A lA) . (cl : compoll nd 22 (A.) I arc shown
Table II - Wang-Ford charges (q,) of the common atoms (x) of 1.2-dihydro-2-phenyl-I.2.4-triazolO[4.3-a)quinoxalin- l -one derivatives
Compd Atoms (x} no. 2 3 4 5 . 6 7 8 9 10 II 12 13 14 15 16 17 18 19 20
2 3 4 5 6 7
8 9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
0.382 -D.27 I -D.074 -D.222 0.155 -D.064 -D.393 0.513 0.308 -D.359 0.808 -D.390 -D.330 -D.534 0.361 -D.249 -D.080 -D.130 -D.I08 -D.152 0.439 -D.351 -D.030 -D.193 -D.09O 0.168 -D. 64 I 0.6920.142 -D.150 0.778 -D.422 -D.302 .-0.5310.424 -0.290 -D.06O -0.132 -D.III -D.174
-D.159 -D.I09 -D.135 -D.105 -D.Oll 0.327 -D.667 0.709 0.178 -D.330 0.835 -D.378 -D.311 -D.543 0.388 -D.280 -D.055 -D.145 -D.087 -D 183 -D.161 -D.I08 -D.l34 -D.I09 -D.005 0.327 -D.668 0.711 0.171 -D.335 0.837 -D.365 -D.307 -0.545 0.380 -D.303 0.100 -0.201 -D.Q63 -0.205 -D.158 -D. II O -D.l33 -D.112 0.001 0.322 -0.664 0.703 0.187 -D.345 0.843 -0.371 -D.3 15 -D.547 0.355 -D.275 -D.078 0.017 -D. I44 -D.153 -D. 159 -0.109 -D.135 -=D.I06 0.000 0.324 -D.662 0.694 0.207 -0.357 0.851 -0.374 -0.322 -0.541 0.4ll -0.385 0.286 -0.236 -0.072 -0.194 -D.157 -O. lll -0.131 -O.1l9 0.012 0.318 -0.664 0.705 0.180 -0.347 0.831 -0.348 -0.305 -0.545 0.251 -D.146 -D.254 0.313 -0.201 -D.l50 -0.160 -0.108 -D.141 -D.091 -0.027 0.333 -0.666 0.695 0.203 -0.329 0.835 -0.392 -0.324 -0.538 0.446 -0.351 -0.107 -0.265 0.053 -0.2 16 -0.136 -0.117 .0.126 -0.139 0.081 0.260 -0.612 0.642 0.261 -0.436 0.879 -0.432 -0.261 -0.545 0.380 -0.265 -0.054 -0.149 -0.081 -0.184 -D.137 -D.117 -0.124 -0.142 0.090 0.257 -0.610 0.640 0.264 -0.447 0.887 -0.429 -0.261 -0.545 0.389 -0.309 0.1l0 -0.190 -0.069 -0.207 -D.135 -0.1 18 -0.123 -D.I44 0.092 0.257 -O.6ll 0.645 0.270 -D.454 0.895 -D.428 -0.264 -0.543 0.400 -0.367 0.289 -0.245 -0.057 -0.202 -D.136 -D.117 -0.129 -0.130 0.067 0.268 -0.618 0.650 0.262 -D.427 0.880 -0.445 -0.265 -0.540 0.438 -0.338 0.109 -0.269 0.068 -0.228 -D.133 -D.118 -0.122 -0. 149 0.103 0.239 -0.582 0.611 0.277 -0.4510.884 -D.435 -0.263 -0.5450.390 -0.276 -0.052 -0.149 -0.080 -0.188 -0.136 -O.1l6 -0.122 -0.146 0.096 0.244 -0.585 0.619 0.257 -D.439 0.879 -D.422 -D.256 -0.546 0.382 -0.296 0.102 -0.204 -0.055 -0.213 -0.133 -D.1l8 -0.121 -D.149 0.102 0.242 -0.582 0.613 0.277 -0.453 0.888 -D.425 -0.265 -0.542 0.405 -0.368 0.289 -0.246 -0.054 -0.208 -D.122 -0.121 -0.120 -D.136 0.048 0.242 -0.600 0.673 0.161 -0.337 0.820 -D.360 -0.298 -0.540 0.377 -0.283 ·-D.050 -0.146 -0.077 -D.189 -0.1 22 -0.126 -0. 122 -D.129 0.042 . 0.268 -0.637 0.710 .. 0.168 -D.366 0.849 -0.392 -D.267 -0.542 0.363 -D.26 I -D.059 -D.I44 -0.084 -D.179 -D.141 -0.120 -D.129 -0.123 0.027 0.307 -D.67 I 0.725 0.173 -0.373 0.863 -D.412 -0.253 -D.543 0.375 -0.271 -0.055 -0.147 -D.081 -0.182 -0.1 55 -0.116 -D.137 -0.109 -D.003 0.346 -D.699 0.724 0.173 -0.3560.856 -0.414 -0.244 -D.542 0.358 -0.25 1 -0.067 -D.143 -D.09O -0.162 -D. I08 -D.129 -D.I04 -D. 158 0.097 0.228 -D.530 0.618 0.211 -D.407 0.865 -D.413 -D.260 -D.540 0.373 -D.252 -D.063 -D.I44 -D.073 -D.201 -D.119 -D.122 -D.I06 -D.153 0.080 0.239 -D.531 0.628 0.178 -D.383 0.863 -D.438 -D.213 -D.538 0.364 -D.245 -0.062 -D.156 -D.065 -0.195 -D.125 -0.122 -D.Ill -0_150 0.078 0.253 -D.535 0.605 0.194 -D.389 0.862 -D.427 -D.234 -D.539 0.371 -D.250 -0.067 -D.145 -D.074 -D.194 -D.123 -D.120 -D.11O -0.150 0.071 0.247 -D.530 0.6180.176 -D.370 0.853 -0.424 -D.224 -0.536 0.355 -D.232 -D.068 -D.157 -D.059 -D.200 -D.132 -O.1l8 -D.113 -0.136 0.04 1 0.284 -D.554 0.6070.210 -D.354 0.841 -0.404 -D.292 -0.537 0.394 -D.27 I -D.064 -D.138 -D.084 -D.193 -D.155 -0.092 -0.125 -0.122 0.013 0.284 -D.496 0.496 0.201 -0.288 0.786 -0.388 -D.256 ...:0.525 0.348 -D.216 -0.092 -D.136 -D.068 -0.199 -D.043 -0.158 -D.064 -0.218 0.347 -0.135 -D.285 0.415 0.383 -D.602 0.856 -0.297 -0.285 -0.541 0.265 -D.214 -0.089 -0.112 -0.107 -0.128 -0.044 -D.158 -D.063 -0.223 0.358 -0.137 -D.286 0.424 0.369 -D.606 0.851 -0.267 -D.281 -D.543 0.234 -0.215 0.060 -0.166 -D.082 -D.145
-D.04O -0.160 -D.06O -D.226 -D.038 -0.161 -D.06O -D.226 -D.034 -0.163 -0.057 -D.235 -0.044 -0.157 -D.069 -0.209
0.032 -0.192 -0.051 -D.227 0.D35 -D.193 -0.048 -D.230 O.oz8 -0.186 -0.062 -0.209 0.002 -0. 184 -0.065 -0.204 0.067 -0.207 -0.043 -0.249
0.362 -D.I44 -0.280 0.413 0.389 -D.617 0.861 -D.283 -D.288 -0.544 0.223 -D.189 -D.125 0.050 -D.152 -D. 107 0.367 -D.149 -D.275 0.405 0.404 -D.625 0.865 -0.286 -D.296 -D.538 0.285 -D.316 0.258 -0.210 -0.09 1 -D.137 0.376 -D.157 -0.274 0.410 0.393 -D.6 18 0.844 -0.273 -D.292 -D.542 0.203 -D.129 -D.257 0.304 -0.177 -D.152 0.336 -D.131 -0.288 0.410 0.394 -D.595 0.850 -0.299 -D.295 -0.537 0.317 -D.283 0.074 -0.240 0.034 -D. I64 0.386 -D.225 -0.093 0.352 0.447 -D.650 0.871 -0.326 -D.301 -0.54 1 0.344 -D.27 I -D.052 -D.143 -D.087 -D.168 0.397 -D.234 -0.086 0.342 0.461 -0.666 0.878 -0.317 , -D.305 -0.543 0.306 -D.256 -D.087 0.020 -D.137 -D.142 0.366 -0.2 13 -0.100 0.356 0.448 -0.633 0.856 -0.330 -0.305 -0.532 0.388 -0.330 0.104 -0.259 0.058 -0.206 0.365 -0.161 -0.198 0.354 0.519 -0.668 0.838 -0.260 -0.364 -0.505 0.239 -0.277 -0.016 -0.1 36 -0.133 -0.074 0.441 -0.263 -0.032 0.335 0.503 -0.744 0.935 -0.361 -0.305 -0.550 0.35 1 -0.273 -0.042 -0.153 -0.084 -0.163
;:<:l o -< 10 C/J » ;:<:l
o 'T]
» o tTl Z o C/J
Z tTl ;:<:l tTl n tTl
~ o ;:<:l
» ~ » o o z C/J -l C/J
+>-00 \0
1490 INDIAN J. CHEM ., SEC B, JUNE 2003
Table 111 - Stepwise development of QSAR equations Model equat ion pKj = I~i Xi + ex
Key Eq. Regress ion Constants (r. c.) Statistics activity no. (pK) (DC) a p, p, ~, p, ps P6 R.,' F AVRES
(s.e.) (s.c.) (s.e.) (s.e.) (s.e.) (s.e .) (s. e.) (ror R) (5) (n)
+1.021 + 1.533 I 0.349 18.1 0.7 16 (0. 166) (0.360) (0.607) (0.846) (33)
2 +0.868 +1.687 I +1 .332 Ico 0.470 15.2 0.605 (0. 159) (0.329) (0.468) 0.709 (0.763) (3)
3 - 1.343 +1.38 1 I + 1.0661co +3.986 q, 0.69 1 24 .9 0.4 17
(0.500) (0.259) (0.362) (0.840) (0. 49) (0.582) (33)
4 - 1.802 +1.548 I +1.1 58 leo +4. 142 qs -4. 12 1 q,. 0.726 22.2 0.387
(0.496) (0.256) (0343) (0.794) ( 1.900) (0. 72) (0548) (33)
5 -3.20 1 +1.422 1 + 1.370 leo +3.595 q, - 5.450 q ,. -7 .285 q l" 0.766 2 1.9 0.377
(0.790) (0.243) (0 .330) (0.770) (2 .288) (2.204) (0.896) (0.507) (33)
A, 6 +1.0161 +0.735 leo +2.884 q, +1 1.254 qu -7.200 q ,o -8. 195 q ,., 0.76'1 58.0 0.369
(0.27 1) (0.329) (0.73 1) (2 .579) (2.579) (2.32 1) (0. 97) (0.503) (33)
7 +0.962 I +0.725 leo +2.795 q, +1 1.555 q" -7.85 1 q' fH '. 0 .776 7 1.5 0.373
(0.244) (0.324) (0698) (2 .47 1 ) (2. 183) (0.896) (0.496) (33)
8 +0.945 I +0.893 leo - 1.974 q7 + 10.047 qu -8.406 q 'h.'~ 0.771 fl9 .9 0.369
(0.248) (0.3 16) (0.507) (2 .465) (2. 164) (0.894) (0.50 1) (33)
9 +0.952 I +0.808 leo + 1.233 q.-7 +9.989 q u -7.428 q' 6.,~ 0.776 7 1.6 0.363
(0245) (03 18) (0.289) (2.273) ( 1.961) (0.897) (0.496) (33)
10 +0.913 I +0.775 Ico + 1.245 q.-7 +10. 128 qu - 7.594 q '6.,'i 0.80 1 87.2 0.344
(25) (0.224) (0.290) (0.269) (2.240) ( 1.980) (0.909) (0.45 3) (32)
II +0.746 I +0.768 leo + 1.253 q.-7 +10.330 q'J - 7.74 1 q".,., 0.:514 9 1.2 0.325
(13,25) (0.2 17) (0266) (0.248) (2.06 1) ( 1.82 1) (0.9 16) (0.4 16) (3 1)
12 - 5.076 - 20.250 q u 0.5 10 15.6 0.50K
(1.466) (5. 129) (0.73 ) (0.627) (15)
13 -4. 111 + 1.502 q, * - 17 .229 tt " 0.5 I 10.7 0 .391
( 1.459) (0.840) (5.035) (0. 0 1) (0.5g0) ( 15)
14 -4.826 -4. 134 q2' - 17.34fl q" 0.584 10.8 0.405
( 1.358) (2.273) (4.989) (0.802) (0.578) ( 15)
A 2A 15 6.369 +3.050 q , +19.623 q" - 8.500 q ", 0.737 14. 1 0 .326
( 1.687) (0.637) (4.43 1 ) (2. 140) (0.89 1) (0.459) ( 15)
16 -4.170 + 1.832 q , - 17.410 q u +2.043 q l7 0.712 12.5 0.3 19
( 1.1 95) (0.709) (4. 178) (0.805) (0. 79) (0.48 1) ( 15)
17 5.255 - 8.236 q, +19.997 q' 2 - 8. 158 q'h 0.723 13.2 0.338
( 1.756) ( 1.787) (4.562) (2. 188) (0. 8 ) (0.47 1 ) ( 15)
18 - 5.042 -4.909 q, - 17 .627 q 'J 1.995 q l7 0.70 12.3 0.329
( 1.224) ( 1.929) (4. 179) (0.807) (0.87 °) (0.484) (15)
19 1. 173 + 1.49 1 q, .3-2 .... +10.154q l2_'J - 1.873 q "~'7 0.735 13.9 0.3 12
(0.307) (0.388) (2. 16 1) (0.573) (0.890) (0.461) ( 15)
(s.e.) (s.e.) (s.e.) (s.e.) (s.e.) (s.e .) (s.c.) (I' or R) (5) (n)
20 1.11 2 +1.327 1'co 0.553 33.2 0.334
(0.089) (0.230) (0.755) (0.425) (27)
2 1 -27.205 +1.437 I 'eo - 52.407 q l4 0.710 32.8 0.267
(7.435) (0 .188) (I 3.759) (0.856) (0 .343) (27)
22 -37.256 + 1.555 I'eo +1.846 q , -7 1.268 q,. 0.07 37.1 0.2 18
(6.701) (0. 157) (0.5 12) ( 12.397) (0.910) (0.280) (27)
A, 23 -36.387 +1.554 1'eo -4.347 q, - 68.254 q '4 O. 07 37.2 0.2 17
(6.5 15) (0. 157) ( 1.202) ( 12.050) (0.91 1) (0280) (27)
24 - 37.004 +1.554 1'eo + 1.297 q '-2 - 70.383 q" 0.807 37.2 0.2 17
(6.64 1) (0 .157) (0.359) ( 12.286) (0.9 11) (0.280) (27)
25 - 36.773 + 1.760 I'cu + 1.290 q' -2 - 69.956 q ,. 0.85 5 1.2 0. 189
(21 ) (5.744) (0 . 152) (0.3 11 ) ( 10.629) (0.93. ) (0.242) (26)
(- Coilld)
Key Eq.
ROY : QSAR OF ADENOSINE RECEPTOR ANTAGONISTS I
Table III - Stepwise development of QSAR equations (- Collld)
Model equation pKj = L~i Xi + a
Regress ion Constant s (r. c.)
1491
Statistics activi ty no. (pK) (DC) a
(s.c.)
26 - 35.494 (2 1,30) (5.304)
27 - 11.843 (5057)
13, (s.c.)
+1.773 I'co (0 140)
+1 .375 I'eo (02 13)
132 (s.c.)
+1.216q '_2 (0.287)
- 0.580 INR ,
(0225)
13, (s.e.)
- 67.556 q" (9 .8 15)
- 23.98 1 q,. (9.375)
Eqs. I - II , 12- 19 and 20-27 explore QSAR of A I> A2A and A, binding affinities respectively .
136 (s.e.)
F (s)
0.882 60.6 (0.947) (0.222)
0.689 (0.849)
22.4 (0.389)
AYRES (n)
0.177 (25)
0.306 (30)
Keys: 95% Cl = 95% confidence intervals of r. c . (df = n- np-i, i = I if intercept is present , i = 0 otherwise); np = no. of predi ctor va ri ables; r.c . are significant at 95% level unless superscripted with * (significant at 90% level ); F ratios are significant at 99% leve l rdf = (np, n - np - i), i = I if inte rcept is present. i = 0 otherwi se]; AC = autocorrelation, DC = Deleted outlier compound
Table IV - Statistical quality of selected* relations of the adenosine AI receptor binding affinity of 1,2-dihydro-2-phenyl I ,2.4-triazolo[4,3-aJquinoxal in- l-one derivatives with Wang-Ford charges of different non-hydrogen common atoms
(alongwith indicator parameters)
Atom no(s)+ (x)
I
3
5
7
9
II
13
15
17
19
1,8
7, 19
8, 13
8, 15
8. 17
8,19 9, 20
1, 8, 19
6,16, 19
7, 16, 19
8, 11,20
8, 13,20
8, 14,20
8, 16, 19
8, 17, 19
8, 18, 20
9, 11 ,20
9, 16, 20
1,8, 16, 19
0.459
0.526
0.62 1
0.660
0.644
0.466
0.454
0.529
0.456
0.479
0.683
0.694
0.680
0.683
0.688
0.726 0.679
0.7 17
0.717
0.749
0.721
0.716
0.720
0.766 0.748
0.729
0.719
0.717
0.757
Model equation pKAI = ~I leo + ~2 1 + L~i+2 q .. + a
r or R
0.7 14
0.756
0.8 10
0.832
0.823
0.7 18
0.711
0.757
0.712
0.726
0.850
0.856
0.849
0.850
0.853
0.872 0.848
0.872
0.872
0.888
0.874
0.872
0.874
0.896 0.887
0.878
0.874
0.872
0.896
10.1 0.770
12.9 0.721
18.5 0.645
2 1.7 0.61 1
20.3 0.625
10.3 0.766
9.9 0.774
13.0 0.71 9
10.0 0.772
10.8 0.756
18.2 0.590
19.2 0.579
18.0 0.592
18.2 0.590
18.6 0.585
22.2 0.548 18.0 0.593
17.2 0.557
17.2 0.558
20. 1 0.525
17.5 0.554
17.2 0.558
17.5 0.554
21.9 0.507 20.0 0.525
18.3 0.545
17.4 0.555
17.2 0.558
17.6 0.5 17
Atom no(s).+ (x)
2 4
6
8 10
12
14
16
18
20
2, 8
8, II
8, 14
8, 16
8. 18
8,20
2,8,19
7, 15, 19
8, II , 19
8, 13 , 19
8, 14.19
8, 15, 19
8, 16,20
8. 17.20
8, 19, 20
9, 16.19
2,8, 16, 19
0.456
0.573
0.618
0.691 0.597
0.543
0.480
0.486
0.455
0.472
0.690
0.688
0.683
0.682
0.682
0.720
0.72 1
0.720
0.726
D.7 17
0.7 17
0.732
0.722
0.726
0.723
0.756
0.757
r or R
0.7 12
0.783
0.809
0.849 0.796
0.766
0.727
0.73 1
0.711
0.722
0.854
0.852
0.850
0.850
0.850
0.869
0.874
0.874
0. 877
0.872
0.873
0.880
0.875
0.877
0.875
0.891
0.896
9.9 0.773
15.3 0.685
18.3 0.647
24.9 0.582 16.8 0.665
13.7 0.708
10.8 0.756
11.1 0.751
9.9 0.773
10.5 0.761
18.8 0.584
18.6 0.586
18.2 0.590
18.2 0.590
18.2 0.59 1
2 1.6 0.554
17.5 0.553
17 .5 0.554
18.0 0.548
17.2 0.558
17.2 0.557
18.5 0.542
17 .6 0.552
18.0 0.548
17.7 0.552
20.9 0.5 17
17.6 0.5 16 (- Coli/d)
1492 INDIAN J. CHEM., SEC B, JUNE 2003
Table IV - Statistica l quality of selected* relations of the adenosine A I receptor binding affinity of I ,2-dihydro-2-phenylI ,2,4-triazolo[4,3-aJquinoxa lin- l-one deri vati ves wi th Wang-Ford charges of di fferent non-hydrogen common atoms
(alongwith indi ca tor parameters) (-Colllell
A tomno(s):
(x)
7, 13, 16, 19
8, 13, 16, 19 8, 16, 19,20
9, 14, 16, 19
0.76 1
0.777 0.759
0.757
M odel equation pKAI = ~I leo + ~2 I + L~;+2 qx; + a
r or R F'" Atom n (5).+ R}
0.898
0.905 0.897
0.896
18.0 0.5 12
20.0 0.495 17.R 0.5 14
17.6 0.5 16
(x)
8, II, 16, 19
8,14, 16, 19
9. I I , 16, 19
9,16, 19,20
0.759
0.762
0.759
0.757
r or R
0.897
0.898
0.897
0.896
17.8 0.5 14
18. 1 0.5 11
17 0.5 14
17.6 0.5 16
* Se lected relations involving charges of the atoms that are not much intercorrelated (r < 0.7) and having corrc lati on coefficients higher than those of the best equati ons involving less number of charge parameters (predictor variables) are shown. +Wang-Ford charges of the atoms or combination of atoms shown are used to deri ve relations.
'" df = np, n - np - I ; n = no. of data points (=33); np = no. of predictor variables
Table V - Stat istica l quali ty of selected* relations of the adenos ine AlA receptor binding affini ty of 1,2-dihydro-2-phenylI ,2,4- triazolo[4,3-a]qu inoxalin- I -one derivati ves with Wang-Ford charges of different non-hydrogen common atoms
A tom no(s).+
(x)
I
3
5
7
9
II
13 15
17
19
1,13 3, 13
5, 13
7, 13
9, 13
I I , 13
13, 15
13, 17
13,1 9
1,7, 13
1, 10, 13
I , II , 13
1, 12, 16 1, 12, 18
1, 13, 15
1, 13, 17 I , 13, 19
2,5, 13
2, 8, 13
2, 10, 13
R 2 a
0.236
0.042
- 0.024
- 0.05 1
- 0.074
0.02 1
0.510 -0.031
-0.0 16
-0.049
0.581 0.548
0.474
0.470
0.476
0.47 1
0.545
0.575
0.532
0.578
0.566
0.608
0.737 0.547
0.586
0.712 0.6 15
0.555
0.574
0.58 1
r or R
0.539
0.333
0.222
0. 154
0.048
0.30 1
0.738 0.207
0.239
0. 162
0.801 0.783
0.74 1
0.739
0.742
0.740
0.78 1
0.797
0.774
0.8 17
0.8 12
0.832
0.891 0.802
0.822
0.879 0.835
0.807
0.8 16
0.8 19
Model equation pK A2A = L~; qx; + a
5.3 0.783
1.6 0.877
0.7 0.907
0.3 0.9 19
0.0 0.929
1.3 0.887
15.6 0.627 0.6 0.9 10
0.8 0.903
0.4 0.9 18
10.7 0.580 9.5 0.603
7.3 0.650
7.2 0.652
7.4 0.649
7.2 0.652
9.4 0.605
10.5 0.584
8.9 0.6 13
7.4 0.582
7.1 0.590
8.2 0.561
14.1 0.459 6.6 0.603
7.6 0.576
12.5 0.481 8.5 0.556
6.8 0.598
7.3 0.585
7.5 0.580
Atom nO(5).+
(x)
2
4
6 8
10
12
14
16
18
20
2, 13 4, 13
6, 13
8, 13
10,13
13, J4
13, 16
13, . 8 13,20
1,8, 13
I , 11 , 12
1, 12, 15
1, 12, 17
1, 13, 14
1, 13, 16
I , 13, 18
1, 13, 20
2,7, 13
2,9, 13
2, 11 , 12
0.229
- 0.008
0.055
0.029
0.047
0.077
- 0.076
0.040
- 0.070
0.045
0.584 0.56 1
0.55 1
0.476
0.47 1
0.470
0.575
0.568
0.482
0.596
0.600
0.566
0.692
0.596
0.68 1
0.624
0.596
0.560
0.554
0.6 16
r or R
0.533
0.252
0.350
0.3 14
0.339
0.378
0.035
0.329
0.080
0.336
0.802 0.790
0.784
0.742
0.739
0.738
0.797
0.794
0.745
0.826
0.828
0.8 12
0.87 1
0.826
0.866
0.839
0.826
0.809
0.806
0.836
s
5.2 0.787
0.9 0.900
1.8 0.87 1
1.4 0.883
1.7 0.875
2.2 0.86 1
0.0 0.929
1.6 0.878
0. 1 0.927
1.7 0.876
10.8 0.578 10.0 0.593
9.6 0.600
7.4 0.649
7.2 0.652
7. 2 0.653
10.5 0.584
10.2 0.589
7.5 0.645
7. 9 0.570
8.0 0.567
7. 1 0.590
11.5 0.497
7.9 0.569
10.9 0.506
8.8 0.549
7.9 0.569
6.9 0.595
6.8 0.598
8.5 0.555 (- Colllel)
ROY : QSAR OF ADENOSINE RECEPTOR ANTAGONISTS r 1493
Table V - Statistical quality of selecled* relations of the adenosine A2A receptor binding affinity of 1,2-dihydro-2-phenyl-I ,2,4-triazoloI4.3-a]quinoxa lin- I-one deri vat ivcs Wilh Wang-Ford charges of different non-hydrogen common atoms
Model equati on pK A2A = L~i q .. + a (-Collld)
Atom no(s)+ R} r or R FV Atom noes): R/ r or R FV
(x) (x)
2, II , 13 0.607 0.831 8.2 0.562 2, 12, 15 0.558 0.808 6.9 0.596
2, 12, 16 0.723 0.885 13.2 0.471 2, 12, 17 0.697 0.873 11.7 0.493
2, 12, 18 0.580 0.8 18 7.4 0.58 1 2, 13, 14 0.587 0.822 7.6 0.576
2. 13, 15 0.583 0.820 7.5 0.578 2, 13.16 0.672 0.862 10.6 0.5 13
2, 13,17 0.708 0.878 12.3 0.484 2. 13, 18 0.630 0.842 8.9 0.545
2. 13, 19 0.624 0.839 8.7 0.550 2. 13.20 0.595 0.826 7.9 0.570
3, II. 13 0.565 0.8 11 7. 1 0.59 1 3, 12, 16 0.6 14 0.835 8.4 0.556
3, 12, 17 0.553 0.806 6.8 0.599 3. 13, 14 0.546 0.802 6.6 0.599
3, 13, 15 0.551 0.804 6.7 0.600 3, 13, 16 0.636 0.845 9.2 0.540
3, 13 17 0.670 0.861 10.5 0.515 3, 13. 18 0.597 0.826 7.9 0.569
3. 13, 19 0.584 0.820 7.5 0.578 4.7.13 0.59 1 0.824 7.7 0.573
4,8. 13 0.604 0.830 8. 1 0.564 4.12.1 5 0.584 0.821 7.6 0.578
4. 12. 16 0.683 0.866 11 .0 0.505 4. 13, 15 0.574 0.8 16 7.3 0.585
4. 13. 16 0.648 0.850 9.6 n.532 4. 13. 17 0.664 0.858 10.2 0.5 19
4, 13. 18 0.603 0.829 8. 1 0.565 4. 13. 19 0.589 0.823 7.7 0.574
4. 13.20 0.572 0.8 15 7.2 0.586 6,8, 12 0.58 1 0.819 7.5 0.580
6.8. 13 0.653 0.853 9.8 0.528 6, 12, 16 0.606 0.831 8.2 0.562
6. 13, 15 0.575 0.8 16 7.3 0.584 6, 13, 16 0.644 0.849 9.4 0.535
6. 13. 17 0.650 0.852 9.7 0.530 6, 13, 18 0.588 0.822 7.7 n.575
6, 13. 19 0.568 (J.8 13 7. 1 0.589 6. 13. 20 (J .557 0.808 6.9 0.596
7. 13,16 0.546 0.802 6.6 0.603 8.9. II 0.565 0.8 11 7. 1 0.59 1
8. 13. 18 0.550 0.804 6.7 0.60 1 10.1 3. 16 0.560 0.809 6.9 0.594
10. 13. 17 0.574 0.8 15 7.3 0.585 10.17.20 0.554 0.806 6.8 0.599
11.I3.16 0.562 0.8 10 7.0 0.593 II. 13, 17 0.565 0.811 7.1 0.59 1
11 . 17.20 0.559 0.808 6.9 0.595 13, 16,20 0.567 0.8 12 7. 1 0.589
13, 17.20 0.58 1 0.8 19 7.5 0.580
*Selcctcd relations in volving charges of the atom, that arc not much intcrcorrclated (r < 0.7) and hav ing correlation coefTi-cien ts hi ghcr than thosc of thc best equati ons involving less num ber of charge paramcters (pred ictor variablcs) are shown. +Wang-Ford charges of the atoms or combination of atoms shown arc used to derive relat ions. v df = np, n - np - I; n = no. of data points (= 15); np = no. of predictor variables
Table VI - Statistical quality of selectcd'" relation s of thc adcnosine A3 receptor binding affin ity of 1.2-dihydro-2-phenyl-1.2.4-triazolof4.3-a Jquinoxalin-l-onc der ivativcs wi th Wang-Ford charges of diffcrcnt non- hydrogen common atoms
(a longwi th indicator paramcters)
Model equati on pKAJ = ~I I'eo + L~i+1 qXI + a
Atom noes): R/ I' or R FV Atom no(s)+ R/ I' or R FV
(x) (x)
I 0.548 0.764 16.8 0.428 2 0.557 0.769 17.3 0.423
3 0.563 0.772 17.7 0.42 1 4 0.582 0.784 19 .1 OA II
5 0.565 0.774 17.9 OA I9 6 0.56 1 0.77 1 17.6 OA22
7 0.540 0.759 16.3 0.43 1 8 0.536 0.756 16.0 0.433
9 0.559 0.770 17.5 0.423 10 0.574 0.779 18.5 0.4 15
II 0.585 0.786 19.4 0.4 10 12 (J .556 0.768 17.3 OA24
13 0.539 (U58 16.2 0.432 14 0.7 J() n.856 32.8 0.343 15 0.584 0.785 19.2 0.411 16 0.562 0.772 17.7 0.42 1
(- Collld)
1494 INDI AN 1. C HEM., SEC B, JUNE 2003
Table VI - Stati stical qua lity of selected* relations of the adenosine AJ receptor binding affinity of L2-dihydro-2-phenyl-I ,2,4-triazolo[4,3-a]quinoxalin-l-one deri vatives with Wang-Ford charges of different non-hydrogen common atoms
(alongwith indicator parameters)
Model equation pKAJ = ~I I'eo + L~i+1 qxi + (l (- Col/ rd)
Atom no(s).+ R} r or R F\7 s Atom no(s).+ R} r or R F\7
(x) (x)
15 0 .584 0.785 19.2 0.411 16 0.562 0.772 17.7 0.421
17 0.540 0 .758 16.3 0.432 18 0 .606 0.798 21.0 0.399
19 0 .604 0.797 20.9 0.400 20 0.582 0 .784 19. 1 0.4 11
1,14 0,/:I()7 0,910 37,1 0,280 2, 14 0,/:107 0,911 37,2 0,279
3, 14 0.794 0.905 34.5 0.288 4,14 0.774 0.894 30.7 0 .303
5, 14 0.725 0.870 23.9 0.333 6,14 0.749 0.882 26 .8 0.3 19
7,14 0.730 0.872 24.4 0.33 1 8,14 0.725 0.870 23.8 0.334
9, 14 0.727 0 .87 1 24.1 0 .332 10, 14- 0.7 13 0.864 22.6 0.34 1
11 , 14 0 .699 0.857 2 1.2 0.349 12, 14 0.7 16 0.865 22.9 0.339
13, 14 0.702 0.858 2 1.4 0.347 14,15 0.7217 0 .866 22.9 0 .338
14,16 0.715 0.865 22.8 0 .339 14,1 7 0.703 0.859 2 1.5 0.346
14, 18 0.724 0.869 23 .7 0.334 14,1 9 0.71 3 0.864 22.5 0.341
14, 20 0 .71 6 0.865 22 .9 0.339
*Se lected rclations in volving charges of the atoms that are not much intercorrelated (r < 0.7) and having correlation coeffi-cients highcr than those of the best equations in volving less number of charge parameters (predictor va ri ables) are shown. +Wang-Ford charges of the atoms or combination of atoms shown are used to deri ve re lations.
\7 df = np, n - np - I ; n = no. of data points (=27); np = no. of predictor variablcs
Table VII - Autocorrelation (r) among important predictor variables (AI binding affinity) (n = 33)
q7 qg qlJ q l6
q7 1.000 0.976 0 .254 0.332
qR 1.000 0 .233 0.335
q lJ 1.000 0 .105
qll> 1.000
ql 9
I
leo
qX-7
q16+19
the best trivariate relation). Again atoms C I, C2, C) and C4 are highly intercorrelated (Table VIII). Considering sign of the charge parameters, a new parameter ql +3-2-4 was defined. Similarl y two more parameters q1 2- 13 and q1 6-17 were defined and Equation 19 was obtained. The calcul ated binding affinity values according to Eq. 19 are g iven in Table I . Autocorrelation among the important predictor variables is presented in Table VIII.
From the studies it appears that the benzene ring of the quioxaline fragment (as evidenced from importance of the atoms C I, C 2, C3 and C4), the phenyl ring present as substituent on the triazole ring
ql 9 leo qH-7 q l6+ 19
0.195 0 .30 1 0.062 0.996 0 .174
0.172 0 .225 0.112 0.992 0.203
0 .226 0.350 0 .5 11 0.247 0 .38 1
0 .629 0.424 0 .158 0.336 0.474
1.000 0.31 1 0 .078 0. 187 0 .385
1.000 0 .164 0.27 1 0 . 152
1.000 0.083 0 .277
1.000 0. 186
1.000
(as evidenced from importance of the atoms C 16, C J7 )
and atoms NI 2 and N I3 (two nitrogens of the triazole ring) are important for adenosine A lA binding affinity.
QSAR of A3 receptor binding affinity No acceptable equation could be generated
considering a ll compounds, quantitati ve A3 binding affi nity data of which were availab le. Some compounds (9, 10, 16, 19, 25~ 33, 35, 36) with low binding affinity were deleted fro m the set for the QSAR study . A dummy parameter {co indicating presence of O=C-C fragment in the a lky lamino group at RI was fo und to singularly explai n 55.3% of the
ROY : QSAR OF ADENOSINE RECEPTOR ANTAGONISTS I 1495
Table VIII - Autocorre lation (r) among important predictor variables (A2A binding affinity) (n = 15)
q l q 2 q 3 q 4 q l2
ql 1.000 0.985 0.942 0.860 0. 135
q2 1.000 0.964 0.8 15 0. 166
q ) 1.000 0.839 0.325
q 4 1.000 0.477
q l2 1.000
q u
q l6
q l7
q1 2·13
Ql b· 17
q l+3.2-4
variance (Table III) . Thi s parameter was retained when correlating di fferent charge parameters and their di fferent combinati ons to the biological acti vity (Table VI). Atoms 0 ,4, C, and and C2 emerged as mos t important atoms. Again , atoms C, and C2 were highl y intercorrelated (Table IX) and hence, a new parameter q' .2 was defined. When a dummy parameter f NRI indi cating the presence o f a lkyl substitutio n on atom N7 (nitrogen) was included, the resulting equation (Eq . 27) could accommodate three more compounds (33, 35, 36). The calculated acti vity va lues accordi ng to Eq. 27 are given in Table I. Autocorre lation among the important predictor variables is presented in Table IX.
From the analys is, it appears that the benzo fused moiety of the quinoxalin ring (as evidenced from impOlt ance of the atoms C, and C2) and oxo group (atom 0 ,4) on the tri azole ring are esssentia l for the A3 binding affinity. Alkyl substitutions o n the nitrogen (N7)
atom of quinoxalin ring are de trimental to the acti vity while presence of acy lamino substituent at R, is conducive to the activity.
Overview of QSA R Based on the above anal yes, the general structure
of the compounds was partitio ned into so me fragments as menti oned below:
(a) Fragmenl A : composed of the quinoxalin nitrogen (N7) with the exocyclic ortho-amino substituent or orth.o-oxo group.
(b) Fragment B : composed o f atoms N ' 2 and N I3
(two nitrogens o f the tri azo le ring) which represents the e lectron rich area.
(c) Fragment C : composed o f phenyl substitutio n on the triazole ring which may be accommodated in the lipophilic si te in the receptor.
q l3 q l6 q l7 q1 2· 13 q 16· 17 q 1+3·2-4
0.336 0.069 0.200 0. 120 0.1 67 0.997
0.320 0.029 0. 180 0.096 0. 14 1 0.989
0. 102 0.065 0.20 1 0.108 0. 166 0.960
0.038 0.051 0. 109 0.265 0.095 0.879
0.732 0.3 11 0.259 0.923 0.276 0. 196
1.000 0.039 0.083 0.938 0.05 1 0.280
1.000 0.938 0.1 37 0.967 0.059
1.000 0. 179 0.995 0. 190
1.000 0. 170 0.058
1.000 0.1 57
1.000
Table IX - Autocorre lation (r) among important predictor vari ab les (A) binding affi nity) (n = 27)
ql q 2 q l4 I'eo INRI q l·2
ql 1.00 0.996 0.394 0. 128 0. 186 1.000
q 2 . 1.000 0.334 0.1 40 0. 188 0.998
q l4 1.000 0.154 0.325 0.377
I'eo 1.000 0.082 0. 131
INRI 1.000 0. 187
ql .2 1.000
(d) Fragment D: representing the oxo group o n the tri azo le ring, which may interact with some hydrogen bond donor group in the receptor.
(e) Fragment E: composed of benzo fu sed moiety of the quinoxalin fragment, which may inte ract wi th planar anchoring site in the receptor.
The above study suggests that fragments A, B and C may be involved in adenosine A, binding while fragments B , C and E may pl ay impo rtant role in adenosine A2A binding. Fragments A, 0 and E may be important for A3 binding. Thus it appears that the requirements fo r optimum binding for these receptor SUbtypes (A" A2A and A3) were di fferent to some extent. However, because of non-ava ilability of all three binding affinity data for all the compounds, quantitati ve se lecti vity re lations could not be generated .
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