A comparison of the binding characteristics of class I antiarrhythmic agents for human muscarinic m1-m3 receptors.
The binding characteristics of the class 1 antiarrhythmic agents, cibenzoline, disopyramide, disopyramide metabolite (the main active metabolite of disopyramide in humans), and pirmenol, for human muscarinic receptors (m1-m3) stably expressed in Chinese hamster ovary cells (CHO) were investigated by binding assay with [3H]N-methylscopolamine ([3H]NMS) as a ligand. All of these agents inhibited the specific [3H]NMS binding to membrane preparations in a concentration-dependent manner. The potencies of affinity of these agents for m1, m2, and m3 receptors (compared by IC50) were disopyramide > pirmenol > disopyramide metabolite > cibenzoline, pirmenol > cibenzoline > disopyramide > disopyramide metabolite, and disopyramide > disopyramide metabolite > pirmenol > cibenzoline, respectively. Some competition curves of cibenzoline, disopyramide, and pirmenol were shallow, and Hill coefficients of these curves differed from unity, suggesting that these agents have allosteric binding characteristics for human muscarinic receptors. The m2-selective ratios to m1 (IC50 m1/IC50 m2) and m3 (IC50 m3/IC50 m2) of cibenzoline were 4.0 and 16, and those of pirmenol were 6.5 and 43, respectively, whereas those of disopyramide and its metabolite ranged from 0.46 to 1.6, suggesting that cibenzoline and pirmenol exerted high selectivity to the m2 receptor. We conclude that (a) all class 1 antiarrhythmic agents in this study have inhibitory effects on human m1, m2, and m3 receptors, and some of those binding may show allosteric characterization; (b) disopyramide and its metabolite have similar affinity to m1 to m3 receptors; and (c) cibenzoline and pirmenol have high m2-selective ratios to m1 and m3.
Medicinal Biology Research Laboratory, Fujisawa Pharmaceutical Co., Osaka, Japan.
N
N
Yamamoto
T
T
Ozaki
Y
Y
Keida
M
M
Ohtsuka
T
T
Goto
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000145:classification / Q000378:metabolism*; D001667:Binding, Competitive; D016466:CHO Cells; D019976:Cloning, Organism; D006224:Cricetinae; D005260:Female; D006801:Humans; D019832:N-Methylscopolamine / Q000378:metabolism*; D010053:Ovary / Q000502:physiology*; D011485:Protein Binding; D011976:Receptors, Muscarinic / Q000235:genetics / Q000502:physiology*
D000889:Anti-Arrhythmia Agents; D011976:Receptors, Muscarinic; D019832:N-Methylscopolamine