Pharmacological profiles of an anticholinergic agent, phencynonate hydrochloride, and its optical isomers

• 来源期刊: 中国药理学报（英文版）
• 关键词: optical isomers muscarinic acetylcholinicreceptors pharmacological profiles radioligand binding assay
• 年，卷（期）: 2005,（5）
• 页码范围: 527-532
• 页数: 6页
• 语种: 英文

摘要

Aim: To comparatively study the pharmacological profiles of 3-methyl-3-azabicyclo (3,3,1)nonanyl-9-α-yl-α-cyclopentyl-α-phenyl-α-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]quinuclidinyl benzilate ([3H] QNB) was R(-)-CPG (Ki=46.49± 1.27 nmol/L)＞CPG (Ki=271.37±72.30 nmol/L)＞S(+)-CPG (Ki=1263.12±131.64 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 ED50±95 % LC value was 21.06±3.04 mg/kg]. CPG and R(-)-CPG displayed nearly equipotent effect in depressing oxotremorineinduced salivation [the ED50±95% LC for R(-) and CPG were 1.10±0.28 and 1.07±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.