In-vivo pharmacological studies of 2-N-carboxamidinonormianserin, a histamine and 5-hydroxytryptamine antagonist lacking central effects.
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-alpha)azepine hydrochloride), a guanidino analogue of mianserin. FCC5 (30-100 micrograms 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 (< or = 1 mg kg-1, i.v.) had no effect on submaximal bronchoconstrictor responses caused by i.v. acetylcholine or the thromboxane A2-mimetic U46619 ((15S)-hydroxy-11 alpha,9 alpha-(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 (< or = 3 mg kg-1, i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)
Leitch
I M
IM
Department of Pharmacology, Monash University, Victoria, Australia.
Boura
A L
AL
Edwards
P
P
King
R G
RG
Rawlow
A
A
Rechtman
M P
MP
D000284:Administration, Oral; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects; D002415:Cats; D002490:Central Nervous System / Q000187:drug effects*; D004487:Edema / Q000188:drug therapy; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*
D006634:Histamine H1 Antagonists; D012702:Serotonin Antagonists; C075499:2-N-carboxamidinonormianserin; D008803:Mianserin; D012701:Serotonin; D006632:Histamine