6-[N,S-dimethyl-N'-cyanothioureidomethyl]-6,11-dihydro-5H- dibenz[b,e]azepine hydrochloride (Fran 12): a histamine and 5-hydroxytryptamine antagonist with pressor properties.
We have synthesized and examined some of the pharmacological properties of 6-[N,S-dimethyl-N'-cyanoisothioureidomethyl]-6,11-dihydro-5H- dibenz(b,e)azepine hydrochloride (Fran 12), a derivative of 6-methylaminomethyl-6,11-dihydro-5H- dibenz[b,e,]azepine. In the guinea-pig isolated ileum, Fran 12 (10(-7)-10(-5) M) caused parallel rightward shifts of the concentration-response curves to histamine. A Schild plot gave a pA2 of 7.48, with a slope not significantly different from -1.0. In the rat stomach fundus strip and in endothelium-denuded aortic rings, Fran 12 inhibited contractile responses to 5-hydroxytryptamine in a non-competitive manner. In both chloralose-anaesthetized and pithed rats, it inhibited pressor responses to 5-hydroxytryptamine. It had no effect on depressor responses to 5-hydroxytryptamine in anaesthetized rats. In pithed rats, Fran 12 (0.25-2 mg/kg, i.v.) produced dose-dependent increases in blood pressure. These were not inhibited by i.v. phentolamine, prazosin, yohimbine, propranolol, methysergide, pentolinium or atropine but were inhibited by verapamil. These results indicate that Fran 12 is a histamine and 5-hydroxytryptamine antagonist which also exerts pressor effects via a peripheral action. The pressor action does not appear to be mediated via effects on alpha 1- or alpha 2-adrenoceptors, muscarinic or nicotinic cholinoceptors or 5-hydroxytryptamine receptors, although calcium channel activation may play a role.
Law
S C
SC
Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
Guyett
F J
FJ
King
R G
RG
Boura
A L
AL
Jackson
W R
WR
Hodgson
W C
WC
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D002319:Cardiovascular System / Q000187:drug effects; D003655:Decerebrate State; D003984:Dibenzazepines / Q000138:chemical synthesis / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013270:Stomach / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D001381:Azepines; D003984:Dibenzazepines; D006633:Histamine Antagonists; D012702:Serotonin Antagonists; C078497:Fran 12; D014700:Verapamil; C015603:azepexole