title: In vitro binding profile and in vivo pharmacological properties of the K-opioid compound PD 117302.
abstract: 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.
authors.affiliation: Istituto di Ricerche Farmacologiche, Mario Negri, Milano, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Colombo
authors.forename: P
authors.initials: P
authors.lastname: Petrillo
authors.forename: A
authors.initials: A
authors.lastname: La Regina
authors.forename: G
authors.initials: G
authors.lastname: Bianchi
authors.forename: A
authors.initials: A
authors.lastname: Tavani
mesh_terms: D000698:Analgesia; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D046508:Culture Techniques; D004174:Diprenorphine / Q000494:pharmacology*; D004231:Diuresis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005772:Gastrointestinal Transit / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D010147:Pain Measurement; D011758:Pyrroles / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism*; D017473:Receptors, Opioid, kappa; D013876:Thiophenes / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D011758:Pyrroles; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D013876:Thiophenes; C054718:PD 117302; D004174:Diprenorphine; D009270:Naloxone