11
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Interaction of Model Opiate Anionic Receptor Sites with Characteristic N-Substituents of Rigid Opiates: PCILO and Empirical Potential Energy Calculations GILDA LOEW, STANLEY BURT, and PAMELA NOMURA Department of Genetics, Stanford University Medical Center, Stanford, CA 94305 ROBERT MACELROY NASA Ames Research Center, Moffett Field, CA 94035 Opiate n a r c o t i c s a r e thought to act a t s p e c i f i c receptors i n the b r a i n s i n c e they e x h i b i t s t e r e o s p e c i f i c b i n d i n g (1) and have been shown by f l u o r e s c e n c e techniques to be l o c a l i z e d a t d i s c r e t e regions i n the c e n t r a l nervous system (2). While much e f f o r t has been made to i s o l a t e and c h a r a c t e r i z e the opiate receptor Ç3), r e l a t i v e l y l i t t l e d e t a i l e d i n f o r m a t i o n e x i s t s about the nature of the o p i a t e b i n d i n g s i t e . Some i n v e s t i g a t o r s d e s c r i b e the receptor as a membrane bound p r o t e i n or proteol i p i d (4) while others have used nerve c e l l components such as cerebroside s u l f a t e or phosphatidyl i n o s i t o l as models f o r the opiate receptor (5). In a d d i t i o n t o the inherent d i f f i c u l t i e s i n c h a r a c t e r i z i n g the opiate r e c e p t o r , the problem i s compounded by the d i v e r s i t y of chemical s t r u c t u r e s which are a c t i v e n a r c o t i c a n a l g e s i c s . The prototypes of r i g i d o p i a t e s a l l have fused r i n g s t r u c t u r e s which may c o n t a i n three (benzomorphans), four (morphinans), f i v e (morphine) or s i x (oripavines/thebaines) fused r i n g s . A l l a c t i v e opiates i n these c l a s s e s , and i n the s o - c a l l e d f l e x i b l e o p i a t e s , e x h i b i t cross tolerance and are r e v e r s i b l y blocked by the opiate antagonist naloxone. In the search f o r a non-addictive a n a l g e s i c , thousands of analogues i n each of these subgroups have been synthesized and t e s t e d . The search has extended to f l e x i b l e c l a s s e s of opiates among which are 4(|>-piperidines, 3c()-piperidines, a c y c l i c compounds such as methadone, and most r e c e n t l y the endogenous peptide o p i a t e s , enkephalins and endorphines. As the number of degrees of freedom i n these c l a s s e s i n c r e a s e s , the resemblance to r i g i d opiates decreases, with the endogenous opiates having only a phenethylamine moiety i n common with r i g i d o p i a t e s . In previous work we have considered how such d i v e r s e c l a s s e s of opiates can be accomodated a t a s i n g l e , expandable opiate receptor and how t h i s accomodation can account f o r observed s t r u c t u r e - a c t i v i t y p r o f i l e s (6, 7_, 8 ) . Within each exogenous opiate f a m i l y there are analogues which are pure a g o n i s t s , pure antagonists and those which a r e mixed a g o n i s t - a n t a g o n i s t s . One c l i n i c a l l y promising 0-8412-0521-3/79/47-112-243$05.00/0 © 1979 American Chemical Society
Olson and Christoffersen; Computer-Assisted Drug Design ACS Symposium Series; American Chemical Society: Washington, DC, 1979.
COMPUTER-ASSISTED DRUG
244
DESIGN
observation i s that i n t h i s l a t t e r group are compounds with low a d d i c t i o n l i a b i l i t y , although many of these have u n d e s i r a b l e psychotomimietic s i d e e f f e c t s (9). The r a t i o of agonist/antagonist potency w i t h i n a given f a m i l y of opiates appears to be modulated by very small changes i n chemical s t r u c t u r e . In r i g i d opiates, the n i t r o g e n i s p a r t of a p i p e r i d i n e r i n g and i s a t e r t i a r y amine which i s thought to act at the receptor s i t e i n i t s protonated form. In fused r i n g opiates the nature of the s u b s t i t u e n t on the amine n i t r o g e n plays a key r o l e i n such modulation; although other groups such as the C-j s u b s t i t u e n t i n o r i p a v i n e s (10) and the substituent i n oxymorphones are a l s o important (11). The extent of agonist/antagonist potency i n a given analogue must be a receptor r e l a t e d event. Opiates are thought to bind and a c t at the receptor by weak, r e v e r s i b l e , non-covalent bonding, i . e . , to form a molecular complex r a t h e r than covalent bonds l e a d i n g to i r r e v e r s i b l e chemical transformations. The conformations of the opiates(which determine how w e l l they f i t at the receptor s i t e ) arid t h e i r e l e c t r o n i c s t r u c t u r e s (which determine t h e i r extent of i n t e r a c t i o n with the receptor) should then be d i r e c t l y r e l e v a n t to t h e i r r e l a t i v e agonist and antagonist potencies. In previous work we have proposed that N-substituents of r i g i d opiates which are mixed agonist-antagonists bind and act at the receptor i n two d i s t i n c t conformations corresponding to two d i f f e r e n t induced receptor s i t e conformations (12). Using t h i s hypothesis, we suggested the s y n t h e s i s of a s e r i e s of new morphine analogues p r e d i c t e d to have a wide range of a g o n i s t / antagonist potency r a t i o s , among which could be a p o t e n t i a l l y u s e f u l , non-addicting a n a l g e s i c . These have been synthesized and show promising r e s u l t s i n p r e l i m i n a r y p r e c l i n i c a l t e s t s (13). E x p l i c i t s t u d i e s of o p i a t e - r e c e p t o r s i n t e r a c t i o n s should be very u s e f u l i n c o n t i n u i n g to explore the f a c t o r s that modulate the extent of agonism and antagonism i n a given o p i a t e and the v a r i a t i o n i n t h i s r a t i o among c l o s e l y r e l a t e d analogues. Such s t u d i e s are s e v e r e l y hampered on the experimental s i d e by the l a c k of a d e t a i l e d d e s c r i p t i o n of the opiate b i n d i n g s i t e . However, every c l a s s of o p i a t e s , i n c l u d i n g the endogeneous peptide o p i a t e s , have i n common an amine group which i s almost completely protonated at p h y s i o l o g i c a l pH. The i n t e r a c t i o n of the quaternized amine group with an a n i o n i c receptor s i t e i s thought to be c e n t r a l to o p i a t e analagesic a c t i v i t y and antagonism. Model receptor s t u d i e s i m p l i c a t e a s u l f a t e or phosphate moiety as p l a u s i b l e a n i o n i c receptor s i t e s (5). In t h i s study, as a f i r s t step i n modeling o p i a t e r e c e p t o r i n t e r a c t i o n s , we have considered the i n t e r a c t i o n of an ammonium ion and methyl s u l f a t e or phosphate with the s e r i e s of compounds shown i n F i g u r e 1. These compounds, as N - s u b s t i t u t e n t s i n r i g i d opiates such as 5,9 dimethyl, 2 hydroxy, 6,7 benzomorphans, e x h i b i t a broad spectrum of pharmacological behavior from f
Olson and Christoffersen; Computer-Assisted Drug Design ACS Symposium Series; American Chemical Society: Washington, DC, 1979.
11.
LOEW
Opiates
E T AL.
245
AMS
AMP
v °
.o H
/ X
o
H'
\ /
Ν H
H
x / C
/ CH
3
M
b) propene
a) ethane/propane H
\
H H
H
/ H
c' Ι
1 3
H
H
CH
H
3
d) methyl cyclopropane
c) benzene
Ο
\
β) 2,3-dimethylfuran
\ ς ) 2-methylfuran
Cr π complexes, an intermolecular coordinate (R ) was defined from the oxygen lone pair to a specified point of the R substituent placed below i t . For benzene, methylcyclopropane, and the four furans the coordinate was the distance from the oxygen lone pair to the center of the ring. For propane and propene the coordinate was the distance from oxygen lone pair to the center of the ^2~^3 hond. At each value of F , rotation of the R-group by 30° intervals about this coordinate axis was made to find the orientation with minimum energy. For the optimum values of R and torsion angle, local geometry relaxation (phosphorous and sulfur atom bond angles) was done to obtain f i n a l values of optimized complex energies. Again, the complex energy was obtained from the difference: Q
Q
q
ΔΕ
η+π
=
[E
complex
"
E
AMP (AMS)
"
Substituent
5
Results and Discussion Table I presents the optimized energies and heavy atom 0-H-R distances obtained by PCILO for Η-bonded complexes of AMP and AMS with the eight substituents studied. The equilibrium distances obtained agree to within 0.1A to those seen in crystals of similar Η-bonded systems (31). While no direct comparison with experiment i s possible, the calculated energies are a l l in a reasonable range of values for H-bond complexes. The AMP forms uniformly better Η-bonds than AMS consistent with the larger heats of hydration observed for phosphate groups. Table I also gives the charge transfer associated with the hydrogen bonded complexes in millielectrons transfered from the AMP or AMS to the substituent. Both AMP and AMS donate approximately the same fraction of electrons to each compound. There i s no obvious correlation between the extent of charge transfer and s t a b i l i t y of the complex formed. Table II gives the optimized energies of the η-*π complexes of AMP and AMS with the eight compounds studied at the minimum energy value of R , the distance from the oxygen atom to the center of the ring or bond in question. While there i s no direct experimental data with which to compare these results, the approximations inherent in the method indicate the minimum distance could be underestimated. Thus we have also calculated the interaction energy at an R distance of 3.2A which i s closer to experimental distances found i n some gas-phase o
Olson and Christoffersen; Computer-Assisted Drug Design ACS Symposium Series; American Chemical Society: Washington, DC, 1979.
Olson and Christoffersen; Computer-Assisted Drug Design ACS Symposium Series; American Chemical Society: Washington, DC, 1979.
12.2 14.8 24.8 13.5
2.96 2.92 2.77 2.92
2.1 2.6 2.6 2.4
8.1 14.6 26.4 10.6
2.89 2.85 2.77 2.86
5.1
5.0
4.9
4.5
ethane
benzene
2-methylfuran^
0
24.9
2.77
3.0
24.9
2.77
5.5
r
m
^
n
= optimized heavy atom distance 0 - H - C.
g) H bonding to H of ring carbon without CH^ substituent.
f) H bonding to ring H on carbon ortho to ring oxygen or sulfur
e) propene 1 = Η-bonding to a l l y l i c H on carbon 3, propene 2 = H bonding to a l l y l i c H on carbon 2
d) millielectrons transferred from AMP or AMS to Ν - substituent
c)
b) -ΔΕ = stabilization energy of optimized complex i n Kcal/mole.
a) AMP/AMS = ammonium methylphosphate/sulfate
methylcyclopropane
2-methylthiofuran
24.7
2.77
3.3
24.9
2.77
5.7
3-methylfuran^
f
27.5
2.92
3.2
22.8
2.85
3.8
c
propene 2
min 15.4
b
2.91
-AE 2.9
c 15.6
min 2.84
b
5.8
-AE
a
AMS
propene 1
Substituent
a
AMP
N-SUBSTITUENTS WITH MODEL ANIONIC RECEPTOR SITES
TABLE I: PCILO CALCULATED ENERGIES AND EXTENT OF CHARGE TRANSFER IN Η-BONDED COMPLEXES OF OPIATE
Olson and Christoffersen; Computer-Assisted Drug Design ACS Symposium Series; American Chemical Society: Washington, DC, 1979. -14.6 -24.9 -26,9
(2.6) (2.2) (2.2) (2.2) (2.1) (2.1)
7.3
7,2
6.8
6,2
4.9
3.1
benzene
3-methylfuran
2nnethylfuran
propene
2,3-dimethyIfuran
propane
E
a
-
-
1.4
aT
-
8.5
17.0
(2.2) (2.4)
8.6
2.1
1.0
2,1
(2.4)
12.3
(2.2)
-
1.0
.6
1.0
0.7
0.9
9.8
3.0
14.2
(2.5)
0.8
1.8 2.8
a
-AE (R=3.2)
6.7
Δρ°
(2.0)
(2.9)
< W
AMS
8.0
-ΔΕ*. min 1.4
2.0
1.6
4,0
5.2
5.3
3.4
5.9
-A (R=3.2)
a) -ΔΕ = S t a b i l i z a t i o n energy of complex expressed i n Kcal/mol. Energy a t *d R = 3.2A obtained by extensive geometry r e l a x a t i o n and t o r s i o n angle v a r i a t i o n of tne model a n i o n i c receptor s i t e . R, expressed i n angstroms, i s the d i s t a n c e from the oxygen atom to the center of the r i n g plane or bond i n question. b) m i l l i e l e c t r o n s t r a n s f e r r e d to AMP from the N-substituents c) m i l l i e l e c t r o n s t r a n s f e r r e d from AMS to the N-substituents
-
-15.6
-89.6
(2.0)
8.2
methylcyclopropane
-42.2
Δρ
A b
(2.6)
AMP
9.1
-ΔΕ , min
3
2-methylthiofuran
Substituent
N-SUBSTITUENTS WITH MODEL ANIONIC RECEPTOR SITES
TABLE I I : PCILO CALCULATED ENERGIES AND EXTENT OF CHARGE TRANSFER IN η-*π COMPLEXES OF OPIATE
11.
LOEW ET Ai,.
Opiates
251
σ π complexes such as that between ethylene and C l ^ (20). A l l the s u b s t i t u e n t s i n v e s t i g a t e d form s t a b l e complexes with both model AMP and AMS a n i o n i c s i t e s but with d i f f e r i n g stabilities. The extent of charge t r a n s f e r i n v o l v e d i n these n-Mr complexes i s a l s o given i n Table I I . I n t e r e s t i n g l y , AMS f u n c t i o n as an e l e c t r o n donor to the s u b s t i t u e n t (η->π) w h i l e AMP f u n c t i o n s as an e l e c t r o n acceptor (η-π complexes obtained frçm the e m p i r i c a l energy program at optimum values of R - 3.2A. We see from t h i s t a b l e that i n t e r a c t i o n energies f o r & I P are comparable to those obtained by the PCILO method at 3.2A. For AMS complexes, the e m p i r i c a l method y i e l d s somewhat l a r g e r energies than those obtained at 3.2A with the PCILO method. For AMP complexes, the major d i f f e r e n c e s i n the PCILO and e m p i r i c a l energy r e s u l t s are: 1) the 2-methylthiofuran forms the most s t a b l e complex with PCILO and one of the l e a s t s t a b l e complexes with the e m p i r i c a l energy method, though the absolute d i f f e r e n c e i n energy i s only 1.8 Kcal/mole: 2) the PCILO method d i f f e r e n t i a t e s the v a r i o u s furan compounds more d i s t i n c t l y than the e m p i r i c a l energy method i n which they a l l form complexes of the same s t a b i l i t y . For the AMS complexes, the major d i f f e r e n c e i n r e s u l t s from the two methods i s that methylcyclopropane forms the most s t a b l e complex with PCILO and one of the l e a s t s t a b l e with the e m p i r i c a l energy method. Both methods given r e l a t i v e l y small e n e r g y v a r i a t i o n s among the compounds at i n t e r a c t i o n distances of 3*2A. The major d i f f e r e n c e s i n the two methods used are that the e m p i r i c a l method does not c o n t a i n terms with e x p l i c i t e l e c t r o n overlap dependence such as a charge t r a n s f e r term but does i n c l u d e t o t a l i n t e r m o l e c u l a r geometry o p t i m i z a t i o n . Figures 2 and 3 show the optimized geometries obtained from both the PCILO and e m p i r i c a l energy methods f o r complexes of AMP and AMS with f i v e of the e i g h t compounds s t u d i e d . The PCILO r e s u l t s give d i s t i n c t η-π complexes i n v o l v i n g i n t e r a c t i o n of one oxygen lone p a i r of e l e c t r o n s with the π-electron system of the s u b s t i t u t e n t . In a l l cases, the e m p i r i c a l energy method gives a t o t a l l y optimized complex which i n v o l v e s mainly e l e c t r o s t a t i c and d i s p e r s i o n terms. As can be seen from Figures 2 and 3, the i n t e r a c t i o n of methylcyclopropane with the model a n i o n i c receptor s i t e i s the one with the g r e a t e s t d i f f e r e n c e o
c
Olson and Christoffersen; Computer-Assisted Drug Design ACS Symposium Series; American Chemical Society: Washington, DC, 1979.
Olson and Christoffersen; Computer-Assisted Drug Design ACS Symposium Series; American Chemical Society: Washington, DC, 1979. ΔΕ
ΔΕ
3.1
4.9
9.1
J
J
3.6 2.1
5.2
J
3.8 1.4
3.8
4.1
1.8
a) Antagonism relative to nalorphine = 1 i n Guinea Pig Ileum (15). b) The 3-methylfurfuryl and 2-methylfurfuryl benzomorphans are equally potent antagonists i n mice and monkeys. No Guinea Pig Ileum Data exists for the 3-methyl analogue c) Stereospecific binding constants Κ from reference (32). d) -ΔΕ = min energy i n Kcal/mole e) Calculated for benzene f) not calculated
propane
0.0
2,3-dimethylfuran
-
e
e
0.024
4.9
e
2-methylthiofuran
e
10.0
0.03
ethylbenzene
7.3
6,2
-
0.22
propene
2.9
4.0
2.8'
5.2
7.2
3.0
0.66
3-methylfuran
1.0
4.2
2.1
5.5
6.8
2.5
0.66
2-methyIfuran
3.8
3.2
8.0
- ΕΜΡ
PCILO
5.2
άΈ,ά
8,2
~
0,8
b
AE
- ΕΜΡ
9
~ PCILO
C
K xl0 e
3.0
a
ANT
me thy Icyclopropane
N-R
AND THEIR ENERGIES OF INTERACTION WITH MODEL ANIONIC RECEPTOR SITES.
TABLE III. ANTAGONIST POTENCY AND BINDING AFFINITY OF BENZOMORPHANS WITH VARYING N-SUBSTITUENTS
Olson and Christoffersen; Computer-Assisted Drug Design ACS Symposium Series; American Chemical Society: Washington, DC, 1979.
2.
I.
i
0
\ \
Λ
b
0
-t-
C
c
^4
d
1 I
f
0
1 1
1
y
1
-/*-
Figure 2. PCILO (Row 1) and empirical (Row 2) optimized geometries of complexes of AMP with (a) methylcyclopropane; (b) benzene; (c) propene; (d) 2,3 dimethyfuran; and (e) 2-methylthiofuran
α
H-fiv
α
e
e
Olson and Christoffersen; Computer-Assisted Drug Design ACS Symposium Series; American Chemical Society: Washington, DC, 1979.
2.
I.
i
ο
o-^o
s
Λ
b
A
M \
À c
c
\
>
> d
d
Figure 3. PCILO (Row 1) and empirical (Row 2) optimized geometries of complexes of AMS with (a) methylcyclopropane; (b) benzene; (c) propene; (d) 2,3-dimethyfuran; and (e) 2-methylthiofuran
α
α
Λ
e
e
11.
LOEW ET AL.
Opiates
255
between the two methods. T h i s geometry d i f f e r e n c e i s r e f l e c t e d i n the d i s p a r i t y i n the energy of t h i s complex obtained by the two methods. Relevance to Opiate A c t i v i t y and Antagonism Antagonist potencies measured i n v i t r o i n the guinea p i g ileum system or i n v i v o by extent of withdrawal i n addicted animals should c l o s e l y p a r a l l e l the a f f i n i t y of opiates f o r the receptor s i t e . Both antagonist potencies and s t e r o s p e c i f i c b i n d i n g constants have been measured f o r a number of N - s u b s t i t u t e d 5,9 dimethyl 2 hydroxy 6,7 benzomorphan analogues (14, 15, 32). Table I I I gives these values f o r the compounds s t u d i e d and shows the extent of c o r r e l a t i o n between the known a f f i n i t i e s and potencies f o r four analogues. Expanding t h i s l i s t to other N-substituents and other r i g i d opiate s e r i e s i n c r e a s e s the c o r r e l a t i o n , though a number of s i g n i f i c a n t d e v i a t i o n s occur (32). In the s e r i e s shown i n Table I I I only the N-substituent i s v a r y i n g . Thus the observed d i f f e r e n c e s i n b i n d i n g a f f i n i t i e s and antagonist potencies could be due d i r e c t l y to d i f f e r e n c e s i n the N-substituent i n t e r a c t i o n s with the receptor s i t e . The c a l c u l a t i o n s reported are an i n i t i a l attempt to determine the extent of i n t e r a c t i o n , i f any, of N-substituents with model a n i o n i c receptor s i t e s . Without the c o n s t r a i n t of a t t a c h i n g the s u b s t i t u e n t to the amine group of the o p i a t e , the e l e c t r o n i c f a c t o r s which c o n t r o l optimium i n t e r a c t i o n s could be more f u l l y explored. As already d i s c u s s e d , s t a b l e complexes were found f o r a l l the s u b s t i t u e n t s i n v e s t i g a t e d but with d i f f e r i n g s t a b i l i t i e s . Even though these compounds are unconstrained by the s t e r i c requirements imposed on them as N-substituents i n r i g i d o p i a t e s , i t i s nevertheless of some i n t e r e s t to compare the c a l c u l a t e d value of i n t e r a c t i o n energy of each compound with the measured a f f i n i t y and/or antagonist potency f o r the most c l o s e l y r e l a t e d benzomorphan analogue. In Table I I I , the compounds studied are l i s t e d i n order of the decreasing antagonist potency they confer as N-substituents of 5,9 dimethyl 2'hydroxy, 6,7 benzomorphans. C a l c u l a t e d s t a b i l i t i e s with both a n i o n i c s i t e s tend to f o l l o w the observed a f f i n i t i e s and p o t e n c i e s . The three most potent antagonists are c a l c u l a t e d to be the three most s t a b l e complexes with AMS and among the four most s t a b l e complexes with AMP. On the other hand, the twa n e a r l y pure agonist have the s m a l l e s t i n t e r a c t i o n energy. For the remaining compounds, the strong complex found f o r 2-methythiofuran does not c o r r e l a t e w e l l with i t s weak antagonism, although there i s no measured b i n d i n g constant f o r t h i s compound. The b i n d i n g constant of pentazocine i s l e s s than expected from the c a l c u l a t e d s t a b i l i t i e s of benzene i n t e r a c t i n g with an a n i o n i c receptor s i t e . In phenazocine, with a phenethyl r a t h e r than phenyl s u b s t i t u e n t , the benzene 1
Olson and Christoffersen; Computer-Assisted Drug Design ACS Symposium Series; American Chemical Society: Washington, DC, 1979.
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r i n g might be too f a r away from the a n i o n i c s i t e f o r optimimum interaction. S i m i l a r trends, but with some d i f f e r e n c e s are seen i n the s t a b i l i t i e s c a l c u l a t e d by the e m p i r i c a l method. With the exception of the cyclopropylmethane, the main discrepancy i s the r e l a t i v e l y l a r g e energy c a l c u l a t e d f o r the 2,3 - dimethylfuran. The s t a b i l i z a t i o n energies of the AMS complexes c a l c u l a t e d by the e m p i r i c a l method c o r r e l a t e more with the measured a f f i n i t i e s and antagonist potencies than those f o r the AMP complexes. A d d i t i o n a l l y , more s t a b l e complexes with AMS a r e found by the e m p i r i c a l method than by the PCILO method. Taken together, the r e s u l t s of both methods i n d i c a t e that e i t h e r the phosphate or s u l f a t e anion i s a reasonable model f o r the a n i o n i c o p i a t e receptor s i t e . The r e s u l t s obtained i n t h i s study, while not d e f i n i t i v e , have been encouraging enough to allow us to continue these s t u d i e s using the same methodology. The next step w i l l be to r e c a l c u l a t e the optimum energies and geometries of the methyl phosphate and s u l f a t e anions i n t e r a c t i n g with these compounds as N-substituents of the p i p e r d i n e r i n g of r i g i d o p i a t e s . I f the two conformer hypothesis of mixed a g o n i s t / antagonist behavior i s c o r r e c t then: a) N-substituent analogues with l i t t l e or no agonist potency should have one w e l l defined, r a t h e r s t a b l e complex b) N-substituent analogues which ftite n e a r l y pure a g o n i s t s should a l s o have one optimum complex, d i s t i n c t from that of a pure antagonist and c) N-substituent analogues with mixed a g o n i s t / a n t a g o n i s t behavior should have two d i s t i n c t s t a b l e r e c e p t o r complexes. The more d i f f e r e n t the s t a b i l i t y of each, the more d i s p a r a t e the a g o n i s t / a n t a g o n i s t potency r a t i o f o r a given o p i a t e should be. The g r e a t e r the s t a b i l i t y of the best complex, the l a r g e r the antagonist potency should be. Work i s now i n progress to t e s t t h i s hypothesis.
Acknowledgement The support of N a t i o n a l I n s t i t u t e of Drug Abuse Grant # DA 00770-03 and NASA Ames Interchange //NCA-OR 745-721 f o r t h i s work i s g r a t e f u l l y acknowledged. The authors a l s o wish t o acknowledge the use of the AIMS computer graphics system a t NASA AMES. Many thanks a l s o to Donald S. Berkowitz and W i l l i a m Maloney f o r help i n the i n i t i a l stages of t h i s study.
Abstract In this study both the PCILO and empirical energy methods were used to characterize intermolecular interactions of typical N-substituents of rigid opiates with model anionic receptor sites. Ammonium methylphosphate (AMP) and ammonium methylsulfate (AMS) were used as model anionic receptor sites. Interaction energies of eight compounds which, as N-substituents, modulate different antagonist/agonist potencies
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in 5,9-dimethyl 2' hydroxy 6,7 benzomorphans were calculated. Stable Η-bonded and n-π complexes were obtained. These results suggest that such complexes could be involved in the mode of interaction of the rigid opiates at the receptor site and in their observed affinities and agonist/antagonist potency ratios. Literature Cited 1. Pert, C. B.; Snyder, S. H. Science, 1973, 179, 1011. 2. Simantov, R.; Snowman, A. M.; Snyder, S. H. Brain Res., 1976, 107, 650. 3. Simon, E. J.; Hiller, J. M.; Edelman, I. Proc. Nat. Acad. Sci. U. S. Α., 1973, 70, 1947. 4. Loewney, L. I.; Schilz, K.; Lowery, P. J.; Goldstein, A. Science, 1974, 183, 749. 5. Loh, H. H . ; Cho, T. M.; Wu, Y. C.; Way, E. L. Life Sci., 1974, 14, 2233. 6. Loew, G. H.; Jester, R. J . Med. Chem., 1975, 18, 105. 7. Loew, G. H.; Berkowitz, D. S.; Newth, R. C. J . Med. Chem. 1976, 19, 863. 8. Loew, G. H.; Burt, S. K. Proc. Nat. Acad. Sci. U. S. Α., 1978, 75, 10. 9. Jasinski, D. R.; Martin, W. R.; Hueldtke, R. Clin. Pharm. Ther., 1971, 12, 613. 10. Lewis, J . W.; Bentley, K. W.; Cowan, A. Annu. Rev. Pharm, 1971, 11, 241. 11. Kosterlitz, H. W.; Waterfield, A. A. Annu. Rev. Pharm., 1975, 15, 29. 12. Loew, G. H.; Berkowitz, D. S. J . Med. Chem., 1975, 18, 656. 13. DeGraw, J. J.; Lawson, J. Α.; Crase, J. L.; Johnson, H. L.; E l l i s , M.; Uyeno, E. T.; Loew, G. H.; Berkowitz, D. S. J . Med. Chem., 1978, 21, 415. 14. Merz, H.; Langbein, Α.; Stockhaus, K.; Walther, G.; Wick, H. in "Narcotic Antagonists", Vol. 8, M. C. Braude, L. S. Harris, E. L. May, J . P. Smith, J . E. Villarreal, Eds., Raven Press: New York, 1974; p.91 15. Kosterlitz, H. W.; Waterfield, Α. Α.; Berthoud, V. in "Narcotic Antagonists," Vol. 8, M. C. Braude; L. S. Harris, E. L. May, J . P. Smith, J . E. Villarreal, eds., Raven Press: New York, 1974, p.319. 16. Diner, S.; Malrieu, S. P.; Jordan, F . ; Gilliert, M. Theor. Chim Acta., 1969, 15, 100. 17. Lochman, R.; Weller, Th. Int. J . Quantum Chem., 1976, 10, 909. 18. Spurling, Τ. H.; Snook, I. K. Chem. Phys Letts., 1975, 32, 159. 19. Weller, Th. Int. J . Quantum Chem., 1977, 12, 805. 20. Lochman, R.; Hofman, H.J. Int. J . Quantum Chem., 1977, 11, 427.
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