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.
Ratner
E I
EI
Cardiology Research Center of the USSR, Moscow.
Baldenkov
G N
GN
Grigorian
G Y
GY
Rosenshtraukh
L V
LV
Tkachuk
V A
VA
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001285:Atropine / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D016293:Moricizine; D009206:Myocardium / Q000378:metabolism; D010640:Phenothiazines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011955:Receptors, Drug / Q000187:drug effects*; D012156:Reticulocytes / Q000187:drug effects / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; D010640:Phenothiazines; D011955:Receptors, Drug; D016293:Moricizine; D001285:Atropine; C046818:ethacizine