title: MR-14134, a new benzothiazepine with central hypotensive action.
abstract: Structural changes introduced into the benzothiazepine molecule have led to a compound, MR-14134 (3-[(3-dimethylamino)propyl]-2,3,4,5- tetrahydro-2[4-methoxyphenyl]-1,5-benzothiazepin-4-one oxalate). We have compared the effects of MR-14134 and diltiazem on blood pressure and heart rate in anaesthetized and pithed rats following intravenous administration as well as in anaesthetized rats after intracerebroventricular administration and on the binding of [3H]clonidine in the rat cerebral cortex. MR-14134 (0.1-5.0 mg/kg, i.v.) produced a dose-dependent hypotensive and bradycardic effect similar in intensity but lasting longer than that of diltiazem. These effects were antagonized by previous administration of yohimbine but not by atropine, propranolol or ICI 118,551. Doses of 1 mg/kg i.v. of MR-14134 did not modify either blood pressure or heart rate in pithed rats and did not affect the hypertensive response elicited by electrical sympathetic stimulation or by exogenous administration of norepinephrine in pithed rats. Intracerebroventricular administration of MR-14134 (60 micrograms/kg) decreased blood pressure and heart rate in rats. This effect was antagonized by yohimbine and prazosin. [3H]Clonidine-binding experiments in the rat cortex showed that neither MR-14134 nor diltiazem have affinity for alpha 2A-adrenoceptors. These results confirmed that MR-14134 has a hypotensive and bradycardic effect in which, unlike diltiazem, the central nervous system is involved. These effects were mediated, at least partly, by alpha 2B-adrenoceptors and I1 imidazoline receptors.
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Pharmacy, University of Salamanca, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Prieto
authors.forename: R
authors.initials: R
authors.lastname: Carrón
authors.forename: M J
authors.initials: MJ
authors.lastname: Montero
authors.forename: A
authors.initials: A
authors.lastname: Morán
authors.forename: L S
authors.initials: LS
authors.lastname: Román
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000378:metabolism / Q000494:pharmacology; D003655:Decerebrate State / Q000503:physiopathology; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D007276:Injections, Intraventricular; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015016:Yohimbine / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; C098113:MR 14134; D015016:Yohimbine; D004110:Diltiazem; D003000:Clonidine