alpha(2)-adrenoceptor antagonist properties of OPC-28326, a novel selective peripheral vasodilator.

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.
AuthorsK Orito, M Kishi, T Imaizumi, T Nakazawa, A Hashimoto, T Mori, T Kambe
JournalBritish journal of pharmacology (Br J Pharmacol) Vol. 134 Issue 4 Pg. 763-70 (Oct 2001) ISSN: 0007-1188 [Print] England
PMID11606316 (Publication Type: Journal Article)
Chemical References
  • Adrenergic alpha-Antagonists
  • Aniline Compounds
  • Azepines
  • OPC 28326
  • Piperidines
  • Quinoxalines
  • Vasodilator Agents
  • Yohimbine
  • Brimonidine Tartrate
  • talipexole
  • 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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: