Comparative study on pharmacological effects of DM-phencynonate hydrochloride and its optical isomers

Abstract

Aim: The 3-azabicyclo(3,3,1)nonanyl-9-α-yl-α-cyclopentyl- α-phenyl-α-glycolate (DM-phencynonate hydrochloride, DMCPG) is a demethylated metabolite of 3-methyl-3-azabicyclo(3,3,1)nonanyl-9-α-yl- α-cyclopentyl-α-phenyl-α-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 subthreshold 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 (Ki=3186 nmol/L) and S(+)DMCPG (Ki=1699 nmol/L) in inhibiting the binding of [3H]QNB. The R(-) and S (+) configurations showed positive cooperation (nH>1) with the muscarinic receptor, whereas (±)DMCPG had a negative cooperation (nH<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 7.78×10-9, 1.88×10 -7, and 1.03×10-7 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 (ED50=0.44 mg/kg)>(±)DMCPG (ED 50=2.88 mg/kg)>S(+)DMCPG (ED50=5.05 mg/kg). Conclusion: (±)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. ©2005 CPS and SIMM.