Pharmacological study of dihydroetorphine in cloned mu-, delta- and kappa-opioid receptors.
We investigated the binding characteristics of dihydroetorphine, 7,8-dihydro-7 alpha-[1-(R)-hydroxy-1-methylbutyl]-6, 14-endoethanotetrahydro-oripavine, and its effect on the inhibitory system of cyclic AMP production using cloned mu-, delta- and kappa-opioid receptors expressed on Chinese hamster ovary cells. The Ki values of dihydroetorphine for the mu-, delta- and kappa-opioid receptors were 4.5 x 10(-10). 1.8 x 10(-9) and 5.7 x 10(-10) M, respectively. On the other hand, those of morphine were 1.9 x 10(-9), 1.4 x 10(-6) and 1.3 x 10(-7) M, respectively. Through all of these three types of opioid receptors, dihydroetorphine inhibited forskolin (10 microM)-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 mu-, delta- and kappa-opioid receptors were 4.2 x 10(-11), 8.6 x 10(-10) and 4.3 x 10(-9) M. respectively. On the other hand, those of morphine were 2.6 x 10(-8), 2.6 x 10(-6) and 1.9 x 10(-6) M, respectively. These results indicate that dihydroetorphine, unlike morphine which preferentially binds the mu-opioid receptor, binds not only mu- but also delta- and kappa-opioid receptors with high affinity and acts as a more potent agonist than morphine for all of the three types of receptors.
Katsumata
S
S
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Minami
M
M
Nakagawa
T
T
Iwamura
T
T
Satoh
M
M
D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D005048:Etorphine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology; D037342:Pertussis Toxin; D017465:Receptors, Opioid, delta / Q000187:drug effects* / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000187:drug effects* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D009292:Narcotic Antagonists; D009294:Narcotics; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D011994:Recombinant Proteins; D010566:Virulence Factors, Bordetella; D005576:Colforsin; D005048:Etorphine; D037342:Pertussis Toxin; C034765:18,19-dihydroetorphine