PD117302: a selective agonist for the κ‐opioid receptor

Open Access
Publisher Website
Google Scholar
Abstract
1 A new nonpeptide κ-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 κ sites and a low affinity at [3H]-[d-Ala2, MePhe4, glyol5]-enkephalin ([3H]-DAGOL) labelled μ sites (Ki = 408 nm) and [3H]-SKF 10047 labelled s sites (Ki = 1.8 μm). 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 κ 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°C, and reversible, with a half-life of dissociation of 3.9 min. 5 Several unlabelled compounds with high affinities for the [3H]-etorphine labelled κ binding site, had comparable affinities when competing for the [3H]-PD117302-specific high affinity binding site. In contrast, DAGOL, [d-Ala2, d-Leu5] enkephalin (DADLE) and [d-Pen2, d-Pen5] enkephalin (DPDPE) had no significant effect on [3H]-PD117302 binding, suggesting minimal interaction with μ and δ binding sites. 6 In autoradiography studies [3H]-PD117302 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).