Interaction of newly synthesized N-cyclopropylmethyl derivatives of (-)-6 beta-acetylthionormorphine with opioid receptors.
1. Analgesic activities of N-cyclopropylmethyl derivatives of (-)-6 beta-acetylthionormorphine, KT-89 and KT-90 and their interactions with opioid receptors were studied. 2. KT-89 and KT-90, as well as morphine inhibited the twitch response of the guinea-pig ileal preparation to electrical stimulation. Their pD2 values indicated that KT-89 and KT-90 are about 6.5 and 10 times as potent as morphine, respectively. In guinea-pig ileal preparation KT-89 and KT-90 also behaved as a mu-antagonist. 3. In rabbit vas deferens which contains kappa-receptors, these substances inhibited the twitch response to electrical stimulation and were about 6 times as potent as dynorphin. 4. Their effects on specific binding of [3H]naloxone (mu-selective ligand), [3H]ethylketocyclazocine (kappa-selective ligand) and [3H]D-Ala2-D-Leu5-enkephalin (delta-selective ligand) to the synaptosomal fractions from rat brain were tested. Though both drugs had a nonselectively high affinity to mu-, kappa- and delta-receptors, affinities of KT-89 and KT-90 to kappa-receptors were about 6 and 13 times higher than that of morphine, respectively. 5. Analgesic activities of KT-89 and KT-90 were 6 and 10 times as potent as morphine in an acetic acid-induced writhing test, and 4 and 5 times as potent in a pressure test. 6. The present results suggest that KT-89 and KT-90 induced analgesic actions are mediated through an activation of kappa-receptors. Both the drugs acted as delta-receptor antagonists. Further experiments are needed to study effects of their property as a delta-antagonist on analgesic action.
Takayanagi
I
I
Department of Chemical Pharmacology, Toho University School of Pharmaceutical Sciences, Chiba, Japan.
Goromaru
N
N
Koike
K
K
Konno
F
F
Mori
T
T
Yoshida
M
M
Kanematsu
K
K
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D004743:Enkephalin, Leucine / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009020:Morphine / Q000494:pharmacology; D009022:Morphine Derivatives / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D010147:Pain Measurement; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014649:Vas Deferens / Q000187:drug effects
D000700:Analgesics; D009022:Morphine Derivatives; D011957:Receptors, Opioid; C058764:KT 88; C065295:KT 90; C065294:KT 89; D009270:Naloxone; D004743:Enkephalin, Leucine; D009020:Morphine