title: alpha(2)-adrenoceptor antagonist properties of OPC-28326, a novel selective peripheral vasodilator.
abstract: 1. Antagonistic properties of OPC-28326 ([4-(N-methyl-2-phenylethylamino)-1-(3,5-dimethyl-4-propionyl-aminobenzoyl)] piperidine hydrochloride monohydrate), a selective peripheral vasodilator, were investigated by analysing the data from functional studies in various tissues from the rat and binding studies of the drug to alpha(2)-adrenoceptor subtypes. 2. Using a human recombinant receptor and rat kidney cortex, we found that OPC-28326 displays affinities to alpha(2A)-, alpha(2B)- and alpha(2C)-adrenoceptors with K(i) values of 2040, 285, and 55 nM, respectively. The K(i) values of yohimbine for alpha(2A)-, alpha(2B)-, and alpha(2C)-adrenoceptors were 3.0, 2.0 and 11.0 nM, respectively. 3. B-HT 920, an alpha(2)-adrenoceptor agonist, produced a pressor response via peripheral postsynaptic alpha(2)-adrenoceptor stimulation (thought to be an alpha(2B)-subtype) in a reserpine-pretreated pithed rat preparation. OPC-28326 (3 - 30 mg kg(-1), i.v.) and yohimbine (0.3 - 3 mg kg(-1), i.v.) caused dose-dependent rightward shift in the pressor dose-response curve induced by B-HT 920. The apparent pA(2) values were 1.55 (0.87 - 2.75, 95% confidence interval) and 0.11 (0.06 - 0.21) mg kg(-1), respectively. The potency of OPC-28326 was about 14 times less than that of yohimbine. 4. Clonidine inhibited the tension developed by electrical stimulation, of the rat vas deferens, by its peripheral presynaptic alpha(2A/D)-adrenoceptor action. OPC-28326 (1 - 100 microM) and yohimbine (10 - 1000 nM) caused a rightward shift in the concentration-response curve of clonidine. The pA(2) values were 5.73 (5.54 - 5.91) and 7.92 (7.84 - 8.01), respectively, providing evidence for a potency of OPC-28326 of about 155 times less than that of yohimbine. 5. Mydriasis was induced by brimonidine via stimulation of central alpha(2A/D)-adrenoceptors in anaesthetized rats. Intravenous OPC-28326 had no effect on this action, even at a very high dose of 10 mg kg(-1) i.v., while yohimbine (0.1 - 0.3 mg kg(-1) i.v.) inhibited mydriasis in a dose-dependent manner, indicating that OPC-28326 was at least 100 times less potent than yohimbine in regard to the anti-mydriatic effect. 6. These data suggest that OPC-28326 preferentially exerts peripheral and postsynaptic antagonistic actions on the alpha(2B)- and alpha(2C)-adrenoceptor subtypes.
authors.affiliation: First Institute of New Drug Research, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Orito
authors.forename: M
authors.initials: M
authors.lastname: Kishi
authors.forename: T
authors.initials: T
authors.lastname: Imaizumi
authors.forename: T
authors.initials: T
authors.lastname: Nakazawa
authors.forename: A
authors.initials: A
authors.lastname: Hashimoto
authors.forename: T
authors.initials: T
authors.lastname: Mori
authors.forename: T
authors.initials: T
authors.lastname: Kambe
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000814:Aniline Compounds / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D000068438:Brimonidine Tartrate; D003655:Decerebrate State; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D015878:Mydriasis / Q000139:chemically induced / Q000517:prevention & control; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D011810:Quinoxalines / Q000008:administration & dosage; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D000814:Aniline Compounds; D001381:Azepines; D010880:Piperidines; D011810:Quinoxalines; D014665:Vasodilator Agents; D015016:Yohimbine; D000068438:Brimonidine Tartrate; C024763:talipexole; C400276:OPC 28326