Hypotensive and alpha-adrenergic activities of 2-(2,3,6-trichlorophenylimino) and 2-(2,3-dichloro-6-methylphenylimino) imidazolidine, two potent derivatives of clonidine.

1 alpha-Adrenergic activities (hypotension, bradycardia, sedation) and affinities of clonidine and two newly substituted derivatives, 2-(2,3,6-trichlorophenylimino)imidazolidine (I) and 2-(2,3-dichloro-6-methylphenylimino)imidazolidine (II), were determined in various in vitro and in vitro models.2 In anaesthetized normotensive rats, the intravenous -log doses (mol/kg) of clonidine, compound I and II required to decrease mean arterial pressure by 20% were 7.96, 8.39 and 7.79, respectively, and to reduce heart rate by 20% were 7.85, 8.23 and 7.91, respectively. Comparable potencies were obtained in vagotomized rats. Following vertebral arterial infusion of clonidine, compound I and II into anaesthetized cats, the -log doses for 20% diminution in mean arterial pressure were 8.72, 9.17 and 7.92, respectively.3 In pithed normotensive rats, the intravenous -log doses (mol/kg) of clonidine, compound I and II required to elevate diastolic pressure by 50 mmHg were 7.49, 7.80 and 8.04, respectively, whereas 50% of the maximal inhibition of electrical stimulation-induced tachycardia was obtained at -log doses of 8.20, 8.25 and 8.34, respectively.4 In mice, the intraperitoneal -log doses (mol/kg) needed for a prolongation of the hexobarbitone-induced loss of the righting reflex by 100% were 6.51, 6.55 and 6.60 for clonidine, compound I and II, respectively.5 Compounds I and II displayed a higher affinity for alpha(1)- and alpha(2)-adrenoceptors than clonidine, identified in rat cerebral membranes by [(3)H]-prazosin and [(3)H]-clonidine.6 The results show that 2,3,6-trisubstituted derivatives of clonidine are potent alpha-adrenoceptor stimulants. This new class of congeners may have potential for pronounced hypotensive activity following systemic application. It is not likely that among members of this series, hypotensive potency can be separated from sedative activity.