CI-926 (3-[4-[4-(3-methylphenyl)-1-piperazinyl]butyl]-2,4-imidazolinedione): antihypertensive profile and pharmacology.
CI-926 (10(-7)-10(-6) M) selectively antagonized the contraction of isolated rabbit aortae to phenylephrine and displaced the alpha-1 adrenoceptor ligand WB4101 (IC50: 82 nM) in rat brain. In the spontaneously hypertensive rat, single oral doses of either CI-926 (0.3-10 mg/kg) or prazosin (0.3-100 mg/kg) caused dose-related reductions in blood pressure; however, CI-926 was more efficacious. The maximal antihypertensive response to CI-926 was unchanged with three consecutive days of oral dosing in the spontaneously hypertensive rat, whereas a first dose effect was noted with prazosin. In two-kidney, one-clip, renal hypertensive rats, CI-926 and prazosin (1-10 mg/kg) lowered blood pressure; however, prazosin was more efficacious. In perinephritic hypertensive dogs, CI-926 (10 mg/kg) lowered blood pressure 20%. In anesthetized dogs, CI-926 in the presence of supermaximal blood pressure-lowering doses of prazosin caused an additional reduction in pressure. With equivalent alpha-1 blockade in anesthetized rats, CI-926 tended to have greater hypotensive activity than prazosin. These results demonstrate that CI-926 is a potent, orally active antihypertensive agent in renin-dependent and -independent hypertension. The profile of CI-926 suggests that it lowers blood pressure in part by interacting with peripheral alpha-1 adrenoceptors and in part via an additional mechanism(s). Although weak relative to its affinity for alpha-1 adrenoceptors, CI-926 was found in preliminary experiments to interact with alpha-2 adrenoceptors, serotonergic receptors and dopaminergic receptors. The importance of these interactions to the blood pressure response of CI-926 remains to be elucidated.
D000317:Adrenergic alpha-Antagonists; D000818:Animals; D000959:Antihypertensive Agents; D001667:Binding, Competitive; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D011224:Prazosin / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D011954:Receptors, Dopamine / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects
D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D007093:Imidazoles; D011942:Receptors, Adrenergic, alpha; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; C048884:CI 926; D011224:Prazosin