Comparative study on pharmacological effects of DM-phencynonate hydrochloride and its optical isomers
Abstract
Aim: 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). (plusminus)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 (Ki=763.75 nmol/L) was 4- and 2-fold more potent than (plusminus)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 (plusminus)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 ED50 values were 2.53 and 18.65 mg/kg, respectively), but (plusminus)DMCPG did not display significant central depressant effects at doses from 10 to 29.15 mg/kg (P>0.05). (plusminus)DMCPG and its optical isomers suppressed the guinea pig ileum contractile response to carbachol. The IC50 values were 7.78times10-9, 1.88times10-7, and 1.03times10-7 nmol/L, respectively. In the anti-salivation study, (plusminus)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)>(plusminus)DMCPG (ED50=2.88 mg/kg)>S(+)DMCPG (ED50=5.05 mg/kg).
Conclusion: (plusminus)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.
Keywords:
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 (Ki=763.75 nmol/L) was 4- and 2-fold more potent than (plusminus)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 (plusminus)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 ED50 values were 2.53 and 18.65 mg/kg, respectively), but (plusminus)DMCPG did not display significant central depressant effects at doses from 10 to 29.15 mg/kg (P>0.05). (plusminus)DMCPG and its optical isomers suppressed the guinea pig ileum contractile response to carbachol. The IC50 values were 7.78times10-9, 1.88times10-7, and 1.03times10-7 nmol/L, respectively. In the anti-salivation study, (plusminus)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)>(plusminus)DMCPG (ED50=2.88 mg/kg)>S(+)DMCPG (ED50=5.05 mg/kg).
Conclusion: (plusminus)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.