Pharmacological study of dihydroetorphine in cloned μ-, δ- and κ-opioid receptors

We investigated the binding characteristics of dihydroetorphine, 7,8-dihydro-7α-[1-(R)-hydroxyl-1-methylbutyl]-6,14-endoethano-tetrahydro-oripavine, and its effect on the inhibitory system of cyclic AMP production using cloned μ-, δ- and κ-opioid receptors expressed on Chinese hamster ovary cells. The K_i values of dihydroetrophine for the μ-, δ- and κ-opioid receptor were 4.5 × 10⁻¹⁰, 1.8 × 10⁻⁹ and 5.7 × 10⁻¹⁰ M, respectively. On the hand, those of morphine were 1.9 × 10⁻⁹, 1.4 × 10⁻⁶ and 1.3 × 10⁻⁷ M, respectively. Through all of these three types of opioid receptors, dihydroetorphine inhibited forskolin (10 μM)-stimulated cyclic AMP production via pertussis toxin-sensitive G protein(s), and the inhibitory effects were antagonized by co-application with opioid receptor antagonists. The IC₅₀ values of dihydroetorphine for the inhibition of cyclic AMP production through the μ-, δ- and κ-opioid receptors were 4.2 × 10⁻¹¹, 8.6 × 10⁻¹⁰ and 4.3 × 10⁻⁹ M, respectively. On the other hand, those of morphine were 2.6 × 10⁻⁸, 2.6 × 10⁻⁶ and 1.9 × 10⁻⁶ M, respectively. These results indicate that dihydroetorphine, unlike morphine which preferentially binds the μ-opioid receptor, binds not only μ- but also δ- and κ-opioid receptors with high affinity and acts as a more potent agonist than morphine for all of the three types of receptors.