Pharmacological profiles of an anticholinergic agent, phencynonate hydrochloride, and its optical isomers
Abstract
Aim: To comparatively study the pharmacological profiles of 3-methyl-3-azabicyclo (3,3,1)nonanyl-9-alpha-yl-alpha-cyclopentyl-alpha-phenyl-alpha-glycolate (phencynonate hydrochloride, CPG), an anticholinergic agent, and its enantiomers [R(–)- and S(+)-CPG].
Methods: The affinity and relative efficacy were tested using radioligand-binding assay with muscarinic acetylcholine receptors from rat cerebral cortex. The pharmacological activities were assessed in three individual experiments: (1) potentiating the effect of subthreshold hypnotic dose of sodium pentobarbital; (2) inhibiting oxotremorine-induced salivation; and (3) inhibiting the contractile response to carbachol.
Results: The order of potency of phencynonate hydrochloride and its optical isomers to inhibit the binding of [3H]quinucli-dinyl benzilate ([3H]QNB) was R(–)-CPG (Ki=46.49plusminus1.27 nmol/L)>CPG (Ki=271.37plusminus 72.30 nmol/L)>S(+)-CPG (Ki=1263.12plusminus131.64 nmol/L). The results showed that R(–)-CPG had the highest affinity to central muscarinic receptors among the three compounds, but did not show any central depressant effects at dose from 10.00 to 29.15 mg/kg. CPG increased the effects of subthreshold hypnotic dose of sodium pentobarbital induced-sleeping [the ED50plusminus95% LC value was 21.06plusminus3.04 mg/kg]. CPG and R(–)-CPG displayed nearly equipotent effect in depressing oxotremorineinduced salivation [the ED50plusminus 95% LC for R(–) and CPG were 1.10plusminus0.28 and 1.07 plusminus 0.15 mg/kg, respectively], and the contractile response to carbachol (pA2 values for R(–) and CPG were 6.84 and 6.80, respectively). S(+)-CPG presented the lowest anticholinergic profiles, but could potentate effects of its enantiomers in some manner.
Conclusions: These data suggested that R(–)-CPG acted as an eutomer in racemate and a competitive antagonist to acetylcholine muscarinic receptors, but S(+)-CPG was less active in comparison to R(–)-CPG and its racemate. The central depressant effects of R(–)-CPG and S(+)-CPG were lower in comparison to its racemate.
Keywords:
Methods: The affinity and relative efficacy were tested using radioligand-binding assay with muscarinic acetylcholine receptors from rat cerebral cortex. The pharmacological activities were assessed in three individual experiments: (1) potentiating the effect of subthreshold hypnotic dose of sodium pentobarbital; (2) inhibiting oxotremorine-induced salivation; and (3) inhibiting the contractile response to carbachol.
Results: The order of potency of phencynonate hydrochloride and its optical isomers to inhibit the binding of [3H]quinucli-dinyl benzilate ([3H]QNB) was R(–)-CPG (Ki=46.49plusminus1.27 nmol/L)>CPG (Ki=271.37plusminus 72.30 nmol/L)>S(+)-CPG (Ki=1263.12plusminus131.64 nmol/L). The results showed that R(–)-CPG had the highest affinity to central muscarinic receptors among the three compounds, but did not show any central depressant effects at dose from 10.00 to 29.15 mg/kg. CPG increased the effects of subthreshold hypnotic dose of sodium pentobarbital induced-sleeping [the ED50plusminus95% LC value was 21.06plusminus3.04 mg/kg]. CPG and R(–)-CPG displayed nearly equipotent effect in depressing oxotremorineinduced salivation [the ED50plusminus 95% LC for R(–) and CPG were 1.10plusminus0.28 and 1.07 plusminus 0.15 mg/kg, respectively], and the contractile response to carbachol (pA2 values for R(–) and CPG were 6.84 and 6.80, respectively). S(+)-CPG presented the lowest anticholinergic profiles, but could potentate effects of its enantiomers in some manner.
Conclusions: These data suggested that R(–)-CPG acted as an eutomer in racemate and a competitive antagonist to acetylcholine muscarinic receptors, but S(+)-CPG was less active in comparison to R(–)-CPG and its racemate. The central depressant effects of R(–)-CPG and S(+)-CPG were lower in comparison to its racemate.