Selectivity for opioid receptor subtypes of enkephalin analogues in isolated smooth muscle and in the analgesic effect in mice.
Selectivity for opioid receptor subtypes of enkephalin analogues (KK-1, -2, -3 and -4) of Tyr moiety on the N-terminal, and Phe-ol group on the C-terminal, connected with the methylene group (n = 1-4) were examined in isolated smooth muscle preparations and in the analgesic effect in mice. In the longitudinal muscle preparations of guinea pig ileum (GPI), morphine, U-50488H and all the enkephalin analogues inhibited electrically evoked contractions, and the inhibitory effects of morphine, KK-1, KK-2 and KK-3 were antagonized by naloxone with relatively high pA2 values, while that of U-50488H and KK-3 were preferentially antagonized by norbinaltorphimine. In the rabbit vas deferens preparations (RVD), on the other hand, U-50488H, KK-3 and KK-4 showed weak inhibitory effects and the inhibition of U-50488H and KK-3 were antagonized by norbinaltorphimine. By intracerebroventricularly (i.c.v.) injection, enkephalin analogues produced analgesia in the acetic acid (AcOH) writhing test, and the effect of KK-1 and KK-2 as well as morphine was antagonized by 1 mg/kg naloxone, while those of U-50488H and KK-3 were sensitive to 1 mg/kg Mr2266. In conclusion, enkephalin analogues with a short methylene chain between the functional groups, KK-1 and KK-2, mainly exert their effect through opioid mu-receptors, while those of longer chain, KK-3 and KK-4, act through kappa-receptors preferentially, and KK-3 is situated in the alternating point of the selectivity for mu- and kappa-receptors.
Watanabe
J
J
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Nagasaki University, Japan.
Takahashi
M
M
Maeda
M
M
Kawasaki
K
K
Kaneto
H
H
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics; D000818:Animals; D001575:Benzomorphans / Q000494:pharmacology; D004558:Electric Stimulation; D004745:Enkephalins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009270:Naloxone / Q000494:pharmacology; D011759:Pyrrolidines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011817:Rabbits; D011957:Receptors, Opioid / Q000187:drug effects*
D000700:Analgesics; D001575:Benzomorphans; D004745:Enkephalins; D011759:Pyrrolidines; D011957:Receptors, Opioid; D009270:Naloxone; C027247:MR 2266; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine