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.
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.
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.
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.
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.
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).
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