In vitro binding profile and in vivo pharmacological properties of the K-opioid compound PD 117302.

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.