In-Vivo Pharmacological Studies of 2-N-Carboxamidinonormianserin, a Histamine and 5-Hydroxytryptamine Antagonist Lacking Central Effects

Abstract

Abstract The in-vivo pharmacological properties have been examined of FCC5 (2-N-carboxamidino-1, 2, 3, 4, 10, 14b-hexahydrodibenzo (c.f.) pyrazino (1, 2-α)azepine hydrochloride), a guanidino analogue of mianserin. FCC5 (30–100 μg kg−1, i.v.) caused long-lasting (>1 h) attenuation of histamine- and 5-hydroxytryptamine (5-HT)-induced bronchoconstriction in the anaesthetized guinea-pig. FCC5 (≤lmg kg−1, i.v.) had no effect on submaximal bronchoconstrictor responses caused by i.v. acetylcholine or the thromboxane A2-mimetic U46619 ((15S)-hydroxy-11α,9α-(epoxymethano)prosta-5Z,13E-dienoic acid). The pressor effects of 5-HT in anaesthetized and pithed rats were inhibited by FCC5 (0·3–1·0 mg kg−1, i.v.). Higher doses of FCC5 (3 mg kg−1, i.v.) reduced bradycardia and depressor responses to 5-HT in anaesthetized rats. In anaesthetized cats and rats and also pithed rats, FCC5 (0·1–1·0 mg kg−1, i.v.) caused sympathomimetic effects as demonstrated by pressor responses and tachycardia. FCC5 (0·1–0·3 mg kg−1, i.v.) inhibited pressor responses to tyramine whereas those to noradrenaline and sympathetic nerve stimulation were potentiated. Oedema in the rat paw caused by intraplantar 5-HT was inhibited by FCC5 (ID50 0·76 mg kg−1, i.p.; and 2·7 mg kg−1, p.o.). In decerebrate rats which had been spinalized at T6–8, fenfluramine-induced facilitation of the flexor reflex of the anterior tibialis muscle was inhibited by mianserin (ID50 0·36 mg kg−1, i.p.) but not by FCC5 (≤3mg kg−1, i.p.). Head twitches in carbidopapretreated mice induced by l-5-hydroxytryptophan were inhibited by mianserin (ID50 0·11 mg kg−1, i.p.), but not by FCC5 (≤30 mg kg−1, i.p.). It is concluded that FCC5 possesses antihistamine and anti-5-HT properties and is orally effective. No evidence was found for central effects.