The Opioid Activity and Receptor Selectivity of Fluorinated Leu⁵ Enkephalin Analogues in Vitro and in Vivo

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The opioid activity and the selectivity for opioid receptor (subtypes) of newly synthesized fluorinated enkephalin (Enk) analogues, [2R, 4R], [2R, 4S], [2S, 4S] and [2S, 4R] trifluoro-Leu⁵-Enk (KKF-31, 32, 33 and 34) were investigated. The inhibitory effect of KKF-compounds on the electrically induced contractions of guinea-pig ileum (GPI) and mouse vas deferens (MVD) were dosedependent but relatively lower than that of L-Leu⁵-Enk, except that KKF-34 was rather slightly more potent than L-Leu⁵-Enk in MVD preparations. In GPI preparations, the pA₂ values of naloxone for these compounds were higher than those of naltrindole while the values of naltrindole for KKF-compound were higher than those of naloxone in MVD preparations. Intracerebroventricular KKF-31 and KKF-32 at doses of 20 and 10 nmol/mouse, respectively, produced analgesia comparable to 0.1 nmol Tyr-D-Arg-Phe-Lys-NH₂ and 100 nmol Tyr-D-Thr-Gly-Phe-Leu-Thr; however, neither KKF-33 nor 34 produced analgesia up to the doses of 100 nmol/mouse. Both naloxone, 1 mg/kg, i.p., and naltrindole, 10 mg/kg, i.p., antagonized KKF-31- and KKF-32-induced analgesia. The results suggest that the introduction of trifluoromethyl group in Leu⁵ results in the alternation of the opioid activity and receptor selectivity. Although KKF-33 and KKF-34 possessed a more potent in vitro inhibitory effect than KKF-31 and KKF-32, mediated through μ- and δ-opioid receptors in both preparations, they did not show any appreciable analgesic effect. KKF-31 and KKF-32 produce naloxone-and naltrindole-reversible analgesia irrespective of in vitro μ- and δ-opioid activity.