Colombo M, Petrillo P, La Regina A, Bianchi G, Tavani A
Istituto di Ricerche Farmacologiche, Mario Negri, Milano, Italy.
Res Commun Chem Pathol Pharmacol. 1991 Jun;72(3):295-306.
The in vitro binding profile and some in vivo pharmacological properties of (+/-)trans-N-Methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzo[b]-thiophene- 4-acetamide (PD 117302) were tested in rats. In rat brain membrane preparation, PD 117302 was selective for the k-binding sites, its KI (3.51 nM) being respectively about 200 and 1300 times lower at k- than at mu- and delta-sites. In vivo, PD 117302 injected intravenously (i.v.) showed dose-related analgesic effects in the 55 degrees C hot-plate test (peak-time 5 min) and in the paw pressure test. In both tests high doses of naloxone were required for full antagonism. PD 117302, injected i.v., produced dose-related diuresis in normally hydrated rats, which was prevented by 2 mg/kg of subcutaneous naloxone or diprenorphine. PD 117302 at doses between 0.125 and 2 mg/kg i.v. did not delay the gastrointestinal transit of a charcoal meal and did not antagonize morphine-induced constipation. Thus PD 117302 has good selectivity for k-binding sites in vitro and induces analgesia and diuresis, but does not slow gastrointestinal transit in vivo, supporting its k-agonist activity.
在大鼠中测试了(±)反式-N-甲基-N-[2-(1-吡咯烷基)-环己基]苯并[b]噻吩-4-乙酰胺(PD 117302)的体外结合特性和一些体内药理学特性。在大鼠脑膜制备中，PD 117302对κ结合位点具有选择性，其解离常数(KI)(3.51 nM)在κ位点分别比在μ和δ位点低约200倍和1300倍。在体内，静脉注射(i.v.)PD 117302在55℃热板试验(峰值时间5分钟)和爪部压力试验中显示出剂量相关的镇痛作用。在这两种试验中，需要高剂量的纳洛酮才能完全拮抗。静脉注射PD 117302在正常水合的大鼠中产生剂量相关的利尿作用，皮下注射2 mg/kg纳洛酮或二丙诺啡可预防这种作用。静脉注射剂量在0.125至2 mg/kg之间的PD 117302不会延迟炭末餐的胃肠运输，也不会拮抗吗啡引起的便秘。因此，PD 117302在体外对κ结合位点具有良好的选择性，并能诱导镇痛和利尿，但在体内不会减缓胃肠运输，这支持了其κ激动剂活性。
