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: K Orito, M Kishi, T Imaizumi, T Nakazawa, A Hashimoto, T Mori, T Kambe
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 134 Issue 4 Pg. 763-70 (Oct 2001) ISSN: 0007-1188 [Print] England
• PMID: 11606316 (Publication Type: Journal Article)

Chemical References

• Adrenergic alpha-Antagonists
• Aniline Compounds
• Azepines
• Piperidines
• Quinoxalines
• Vasodilator Agents
• Yohimbine
• Brimonidine Tartrate
• talipexole
• OPC 28326

Topics

• Adrenergic alpha-Antagonists (metabolism, pharmacology)
• Aniline Compounds (metabolism, pharmacology)
• Animals
• Azepines (pharmacology)
• Binding, Competitive
• Blood Pressure (drug effects)
• Brimonidine Tartrate
• Decerebrate State
• Dose-Response Relationship, Drug
• In Vitro Techniques
• Male
• Muscle Contraction (drug effects)
• Mydriasis (chemically induced, prevention & control)
• Piperidines (metabolism, pharmacology)
• Quinoxalines (administration & dosage)
• Radioligand Assay
• Rats
• Rats, Sprague-Dawley
• Synaptic Transmission (drug effects)
• Vas Deferens (drug effects, physiology)
• Vasodilator Agents (pharmacology)
• Yohimbine (pharmacology)