ABSTRACT
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.
Subject(s)
Blood Pressure/drug effects , Dibenzazepines/pharmacology , Histamine Antagonists/pharmacology , Serotonin Antagonists/pharmacology , Adrenergic alpha-Agonists/pharmacology , Anesthesia , Animals , Aorta, Thoracic/drug effects , Azepines/pharmacology , Cardiovascular System/drug effects , Decerebrate State , Dibenzazepines/chemical synthesis , Female , Guinea Pigs , Ileum/drug effects , In Vitro Techniques , Male , Rats , Rats, Wistar , Stomach/drug effects , Verapamil/pharmacologyABSTRACT
1. Some guanidines, related in structure to mianserin and to 2-methyl-1,2,9,13b-tetrahydro-3H-dibenz[c,f]imadazo[1,5a] azepin-3-imine hydrobromide (WAL 801), have been synthesized and shown to be peripherally acting 5-HT2 antagonists. Structurally related compounds but not bearing a charged ionic group have been shown to have central activity. 2. Computer-aided molecular modelling has been used to establish a 5-HT2 pharmacophore. 3. The principle of exclusion from the CNS by incorporating a highly polar group to a biologically active molecule has been extended to the design and synthesis of a peripherally acting analgesic.
