Pharmacological profiles of an anticholinergic agent, phencynonate hydrochloride, and its optical isomers.
OBJECTIVE
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]quinuclidinyl benzilate ([3H]QNB) was R(-)-CPG (K(i)=46.49+/-1.27 nmol/L)>CPG(K(i)=271.37+/-72.30nmol/L)>S(+)-CPG(K(i)=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 oxotremorine-induced 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 (pA(2) 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.
Wang
Li-yun
LY
Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
Wang
Yun
Y
Zheng
Jian-quan
JQ
Zhong
Buo-hua
BH
Liu
He
H
Dong
Si-jian
SJ
Ruan
Jin-xiu
JX
Liu
Ke-liang
KL
D000818:Animals; D001372:Aza Compounds / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D002217:Carbachol / Q000037:antagonists & inhibitors; D002540:Cerebral Cortex / Q000378:metabolism*; D018680:Cholinergic Antagonists / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006016:Glycolates / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D006993:Hypnotics and Sedatives / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects*; D010095:Oxotremorine / Q000037:antagonists & inhibitors; D010424:Pentobarbital / Q000037:antagonists & inhibitors; D011813:Quinuclidinyl Benzilate / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012472:Salivation / Q000187:drug effects; D012890:Sleep / Q000187:drug effects; D013237:Stereoisomerism
C504860:3-methyl-3-azabicyclo(3,3,1)nonanyl-9-alpha-yl-alpha-cyclopentyl-alpha-phenyl-alpha-glycolate; D001372:Aza Compounds; D018680:Cholinergic Antagonists; D006016:Glycolates; D006993:Hypnotics and Sedatives; D011976:Receptors, Muscarinic; D010095:Oxotremorine; D011813:Quinuclidinyl Benzilate; D002217:Carbachol; D010424:Pentobarbital