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

详细信息    查看全文

• 作者：Yaeko Tsukahara-Ohsumi ; Fumio Tsuji ; Masashi Niwa ; Mikiko Nakamura ; Keiko Mizutani ; Naoki Inagaki ; Minoru Sasano ; Hiroyuki Aono
• 关键词：SA14867 ; Kappa-opioid receptor agonist ; Nociceptive pain ; Pruritus
• 刊名：European Journal of Pharmacology
• 出版年：2010
• 出版时间：25 November 2010
• 年：2010
• 卷：647
• 期：1-3
• 页码：62-67
• 全文大小：853 K

文摘

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 ED₅₀ 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 ED₅₀ 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.