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

Abstract

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 IC 50 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.