title: 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.affiliation: Research and Development Center, Santen Pharmaceutical Co., Ltd., Ikoma-shi, Nara, Japan.
authors.forename: Yaeko
authors.initials: Y
authors.lastname: Tsukahara-Ohsumi
authors.forename: Fumio
authors.initials: F
authors.lastname: Tsuji
authors.forename: Masashi
authors.initials: M
authors.lastname: Niwa
authors.forename: Mikiko
authors.initials: M
authors.lastname: Nakamura
authors.forename: Keiko
authors.initials: K
authors.lastname: Mizutani
authors.forename: Naoki
authors.initials: N
authors.lastname: Inagaki
authors.forename: Minoru
authors.initials: M
authors.lastname: Sasano
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aono
mesh_terms: D000700:Analgesics / Q000378:metabolism / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000982:Antipruritics / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015289:Leukotrienes / Q000008:administration & dosage / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D010147:Pain Measurement; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000187:drug effects; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000187:drug effects / Q000378:metabolism; D013644:Tartrates / Q000378:metabolism* / Q000494:pharmacology*; D013844:Thiazoles / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: C556960:3-acetyl-6-chloro-2-(2-(3-(N-(2-ethoxyethyl)-N-isopropylamino)propoxy)-5-methoxyphenyl)benzothiazoline O,O'-diacetyl-L-tartrate; D000700:Analgesics; D000701:Analgesics, Opioid; D000982:Antipruritics; D015289:Leukotrienes; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013644:Tartrates; D013844:Thiazoles; C025348:arachidonic acid 5-hydroperoxide; D009020:Morphine