Open AccessComparative study on pharmacological effects of DM‐phencynonate hydrochloride and its optical isomers 1
Author(s) -
WANG Liyun,
ZHENG Jianquan,
WANG Yun,
ZHONG Bohua,
RUAN Jinxiu,
LIU Keliang
Publication year - 2005
Publication title -
acta pharmacologica sinica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.514
H-Index - 90
eISSN - 1745-7254
pISSN - 1671-4083
DOI - 10.1111/j.1745-7254.2005.00183.x
Subject(s) - muscarinic acetylcholine receptor , chemistry , oxotremorine , pharmacology , hydrochloride , muscarinic acetylcholine receptor m1 , carbachol , stereochemistry , alpha (finance) , enantiomer , pentobarbital , receptor , biochemistry , medicine , construct validity , nursing , patient satisfaction
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 oxotremorineinduced salivation; and (3) inhibiting the contractile response to carbachol. Results: In the competitive binding assay, R(−)DMCPG (K 1 =763.75 nmol/L) was 4‐ and 2‐fold more potent than (±)DMCPG (K 1 =3186 nmol/L) and S(+)DMCPG (K 1 =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 7.78×10 −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 (ED 50 =0.44 mg/kg)>(±)DMCPG (ED 50 =2.88 mg/kg)>S(+)DMCPG (ED 50 =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.