SA14867, a newly synthesized kappa-opioid receptor agonist with antinociceptive and antipruritic effects.

Abstract

SA14867 ((+)-3-Acetyl-6-chloro-2-[2-(3-(N-(2-ethoxyethyl)-N-isopropylamino)propoxy)-5-methoxyphenyl]benzothiazoline O,O'-diacetyl-L-tartrate), a selective kappa-opioid receptor agonist, was synthesized and its antinociceptive and antipruritic effects were investigated. In a functional binding assay, SA14867 showed approximately more than 31,000 and 2200 fold higher affinity for the kappa-opioid receptor than for the mu- and delta-opioid receptors, respectively. SA14867 inhibited acetic acid-induced writhing and formalin test results after oral administration. The ED(50) values of SA14867 for acetic acid-induced writhing and for formalin test first phase and second phase were 1.9, 9.4, and 6.4 mg/kg, respectively. These values were smaller than those of asimadoline, U-50488H, and tramadol. SA14867 also showed antinociceptive effects in silver nitrate-induced arthritis that were as strong as U-50488H, tramadol, and morphine, and were stronger than asimadoline. The ED(50) value of SA14867 for hyperalgesia of arthritis was approximately 10 mg/kg. In addition, SA14867 showed antipruritic effects on 5-hydroperoxyeicosatetraenoic acid (HPETE) and substance P-induced pruritic models at 1 to 3 mg/kg. SA14867 also attenuated scratching reactions in a morphine-induced pruritic model in monkeys. Some of the inhibitory effects of SA14867 on nociceptive and pruritic models were attenuated by a kappa-opioid receptor antagonist, nor-BNI. These results suggest that SA14867 is a potential antinociceptive and antipruritic drug.

• Authors: Yaeko Tsukahara-Ohsumi, Fumio Tsuji, Masashi Niwa, Mikiko Nakamura, Keiko Mizutani, Naoki Inagaki, Minoru Sasano, Hiroyuki Aono
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 647 Issue 1-3 Pg. 62-7 (Nov 25 2010) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 20813108 (Publication Type: Journal Article)
• Copyright: Copyright © 2010 Elsevier B.V. All rights reserved.

Chemical References

• 3-acetyl-6-chloro-2-(2-(3-(N-(2-ethoxyethyl)-N-isopropylamino)propoxy)-5-methoxyphenyl)benzothiazoline O,O'-diacetyl-L-tartrate
• Analgesics
• Analgesics, Opioid
• Antipruritics
• Leukotrienes
• Receptors, Opioid, delta
• Receptors, Opioid, kappa
• Receptors, Opioid, mu
• Tartrates
• Thiazoles
• arachidonic acid 5-hydroperoxide
• Morphine

Topics

• Analgesics (metabolism, pharmacology)
• Analgesics, Opioid (metabolism, pharmacology)
• Animals
• Antipruritics (metabolism, pharmacology)
• Dose-Response Relationship, Drug
• Humans
• Leukotrienes (administration & dosage, metabolism)
• Macaca mulatta
• Male
• Morphine (administration & dosage, metabolism, pharmacology)
• Pain Measurement
• Rats
• Rats, Wistar
• Receptors, Opioid, delta (agonists, drug effects)
• Receptors, Opioid, kappa (agonists, drug effects)
• Receptors, Opioid, mu (agonists, drug effects, metabolism)
• Tartrates (metabolism, pharmacology)
• Thiazoles (metabolism, pharmacology)