[3H]U69,593 binding in guinea-pig brain: comparison with [3H]ethylketazocine binding at the κ-opioid sites

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Abstract
[3H]U69,593 and [3H]ethylketazocine (μ + δ suppressed) binding was measured in homogenates of guinea-pig brain. Both ligands bind with high affinity to a single class of opioid sites. The relative equilibrium dissociation constant (KD) for [3H]U69,593 is 1.15 nM, while [3H]ethylketazocine has a KD value of 0.33 nM. Their respective maximum binding capacities are 4.49 and 4.48 pmol/g of wet tissue. Various μ-selective, δ-selective, κ-selective, and nonselective opioids were tested in competition studies against the binding of [3H]U69,593 or [3H]ethylketazocine (in the presence of μ- and δ-blockers) to measure their relative affinity. [D-Ala2, MePhe4,Gly5-ol]enkephalin (μ-selective) has low affinity (600–3000 nM) and [D-Pen2,D-Pen5]enkephalin and [D-Ser2, Leu5, Thr6]enkephalin (δ-selective) have very low affinities (> 20 000 nM) at the sites labelled with [3H]U69,593 or [3H]ethylketazocine. On the other hand, unlabelled U69,593, U50,488H, and tifluadom (all three κ-selective substances) display high affinity (1–5 nM) at those sites. Nonselective opioids, such as bremazocine, levorphanol, and ethylketazocine show similar affinities at the sites labelled with [3H]U69,593 and at the sites labelled with [3H]ethylketazocine. These data indicate that [3H]U69,593 is a selective high-affinity ligand for the same sites that are labelled with [3H]ethylketazocine (in the presence of μ- and δ-blockers) and that these are κ-sites.

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