title: PD117302: a selective agonist for the kappa-opioid receptor.
abstract: 1. A new nonpeptide kappa-opioid compound, a cyclohexyl benzeneacetamide derivative (PD117302), has been synthesized and its affinity for the different types of opioid receptor determined. The ability of PD117302 to modify the activity of the electrically-stimulated guinea-pig ileum and rabbit vas deferens has also been evaluated. 2. In binding studies using guinea-pig brain homogenates, unlabelled PD117302 had a high affinity (Ki = 3.7 nM) at [3H]-etorphine labelled kappa sites and a low affinity at [3H]-[D-Ala2, MePhe4, glyol5]-enkephalin ([3H]-DAGOL) labelled mu sites (Ki = 408 nM) and [3H]-SKF 10047 labelled sigma sites (Ki = 1.8 microM). In bioassay studies, PD117302 was a potent agonist, producing a maximum inhibition of the electrically-evoked contractions of the guinea-pig ileum (IC50 = 1.1 nM) and rabbit vas deferens (IC50 = 45 nM) which was naloxone-reversible. 3. In guinea-pig brain, [3H]-PD117302 bound to a high-affinity opioid binding site with a KD of 2.7 nM and a Bmax of 3.4 pmol g-1 wet weight. The Bmax was found to be less than 50% of the Bmax values for [3H]-etorphine and [3H]-bremazocine suggesting that [3H]-PD117302 may be a specific ligand for a subtype of kappa receptor. [3H]-PD117302 also bound with micromolar affinity to a non-opioid binding site. 4. Kinetic studies found that [3H]-PD117302-specific binding to the high affinity site was saturable, reaching equilibrium within 20 min at 4 degrees C, and reversible, with a half-life of dissociation of 3.9 min. 5. Several unlabelled compounds with high affinities for the ['H]-etorphine labelled K binding site, had comparable affinities when competing for the ['H]-PDl 17302-specific high affinity binding site. In contrast, DAGOL, [D-Ala', D-Leu'] enkephalin (DADLE) and [D-Pen2, D-Pen'] enkephalin (DPDPE) had no significant effect on ['H]-PD 1 17302 binding, suggesting minimal interaction with mu and delta binding sites. 6. In autoradiography studies ['H]-PD1 17302 binding sites were found throughout the brain with the greatest density in the striatum, cerebral cortex (layers V-VI), substantia nigra, and the molecular layer of the cerebellum. Lowest levels were found in the granular layer of the cerebellum, thalamus and cerebral cortex (layers I - IV).
authors.affiliation: Parke-Davis Research Unit, Addenbrookes Hospital Site, Cambridge.
authors.forename: C R
authors.initials: CR
authors.lastname: Clark
authors.forename: B
authors.initials: B
authors.lastname: Birchmore
authors.forename: N A
authors.initials: NA
authors.lastname: Sharif
authors.forename: J C
authors.initials: JC
authors.lastname: Hunter
authors.forename: R G
authors.initials: RG
authors.lastname: Hill
authors.forename: J
authors.initials: J
authors.lastname: Hughes
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004558:Electric Stimulation; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D011817:Rabbits; D011957:Receptors, Opioid / Q000187:drug effects* / Q000378:metabolism; D017473:Receptors, Opioid, kappa; D013876:Thiophenes / Q000494:pharmacology*; D014649:Vas Deferens / Q000187:drug effects
chemical_list: D011758:Pyrroles; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D013876:Thiophenes; C054718:PD 117302