Comparative study on pharmacological effects of DM-phencynonate hydrochloride and its optical isomers.
OBJECTIVE
The 3-azabicyclo(3,3,1)nonanyl-9-alpha-yl-alpha-cyclopentyl-alpha-phenyl-alpha-glycolate (DM-phencynonate hydrochloride, DMCPG) is a demethylated metabolite of 3-methyl-3-azabicyclo(3,3,1)nonanyl-9-alpha-yl-alpha-cyclopentyl-alpha-phenyl-alpha-glycolate (phencynonate hydrochloride, CPG). (+/-)DMCPG had one chiral center and two enantiomers [R(-) and S(+)DMCPG]. Here we carried out a comparative study of the pharmacological profiles of these optical isomers.


METHODS
Affinity and relative efficacy were tested using a radioligand-binding assay with muscarinic acetylcholine receptors from the rat cerebral cortex. Pharmacological activity was assessed in three individual experiments: (1) potentiating the effect of a sub-threshold hypnotic dose of sodium pentobarbital; (2) inhibiting oxotremorine-induced salivation; and (3) inhibiting the contractile response to carbachol.


RESULTS
In the competitive binding assay, R(-)DMCPG (K(i)=763.75 nmol/L) was 4- and 2-fold more potent than (+/-)DMCPG (K(i)=3186 nmol/L) and S(+)DMCPG (K(i)=1699 nmol/L) in inhibiting the binding of [(3)H]QNB. The R(-) and S (+) configurations showed positive cooperation (n(H)>1) with the muscarinic receptor, whereas (+/-)DMCPG had a negative cooperation (n(H)<1) relationship with the muscarinic receptor in a radio-binding assay. Both the R(-) and S(+) configurations could potentiate the effect of sub-threshold hypnotic dose of sodium pentobarbital in a dose-dependent manner (the ED(50) values were 2.53 and 18.65 mg/kg, respectively), but (+/-)DMCPG did not display significant central depressant effects at doses from 10 to 29.15 mg/kg (P>0.05). (+/-)DMCPG and its optical isomers suppressed the guinea pig ileum contractile response to carbachol. The IC(50) values were 7.78 x 10(-9), 1.88 x 10(-7), and 1.038 x 10(-7) nmol/L, respectively. In the anti-salivation study, (+/-)DMCPG and its enantiomers depressed oxotremorine- induced salivation in a dose-dependent manner, and the order of potency was R(-)DMCPG (ED(50)=0.44 mg/kg) > (+/-)DMCPG (ED(50)=2.88 mg/kg) >S(+)DMCPG (ED(50)=5.05 mg/kg).


CONCLUSIONS
(+/-)DMCPG and its optical isomers have differences in their pharmacological potencies as anticholinergic agents, and the R(-) configuration is more active than the S(+) configuration.
Wang
Li-yun
LY
Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
Zheng
Jian-quan
JQ
Wang
Yun
Y
Zhong
Bo-hua
BH
Ruan
Jin-xiu
JX
Liu
Le-liang
LL
D000818:Animals; D001372:Aza Compounds / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D002217:Carbachol / Q000037:antagonists & inhibitors; D002540:Cerebral Cortex / Q000378:metabolism*; D005260:Female; D006016:Glycolates / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects*; D010095:Oxotremorine / Q000037:antagonists & inhibitors; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D012472:Salivation / Q000187:drug effects; D013237:Stereoisomerism
C504860:3-methyl-3-azabicyclo(3,3,1)nonanyl-9-alpha-yl-alpha-cyclopentyl-alpha-phenyl-alpha-glycolate; D001372:Aza Compounds; D006016:Glycolates; D010095:Oxotremorine; D011813:Quinuclidinyl Benzilate; D002217:Carbachol