Moracizine and ethacizine effects on membrane receptors

Interaction of the antiarrhythmics moracizine (moricizine, ethmozine, ETHM) and ethacizine (ETHA), the ethyl ester hydrochlorides of 10-(3-R-propionyl)-phenothiazine-2-carbamic acid (where R is morpholine or diethylamine, respectively), with muscarinic cholinergic alpha- and beta-adrenergic systems and histamine H1 receptors (H1-R) has been studied. ETHA and ETHM displaced [3H]-quinuclidinyl benzilate ([3H]-QNB) from muscarinic receptors of M2 type (M2-R) of rabbit heart with Ki = 0.65 +/- 0.07 and 21 +/- 1 mumol/l in atria, 0.77 +/- 0.06 and 22 +/- 3 mumol/l in ventricles; [3H]-pirenzepine ([3H]-PZ) from M1-R of rabbit brain cortex with Ki = 0.70 +/- 0.04 and 3.1 +/- 0.1 mumol/l, respectively. However, only ETHA inhibited the effect of carbachol on rabbit heart adenylate cyclase (AC). ETHM and ETHA bound to alpha 1- and alpha 2-adrenergic receptors (AR) and H1-R of rabbit brain cortex with an affinity in the range of 7-50 mumol/l. Both drugs did not influence epinephrine-sensitive AC of human platelets in concentrations up to 100 mumol/l. They neither bound to beta 1-AR of rabbit heart and beta 2-AR of rat reticulocytes, nor influenced the regulation of AC by isoprenaline (isoproterenol) in the same membrane preparations in concentrations up to 100 mumol/l. The present data shows that ETHA and ETHM in therapeutic doses may have M-cholinolytic properties, ETHA being more potent than ETHM. Coupled with the results of other investigators it might explain the wider spectrum of clinical effects of ETHA as compared with ETHM.