title: The opioid activity and receptor selectivity of fluorinated Leu5 enkephalin analogues in vitro and in vivo.
abstract: 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 dose-dependent 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 mu- and delta-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 mu- and delta-opioid activity.
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Nagasaki University, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Watanabe
authors.forename: S
authors.initials: S
authors.lastname: Tokuyama
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
authors.forename: H
authors.initials: H
authors.lastname: Kaneto
authors.forename: M
authors.initials: M
authors.lastname: Maeda
authors.forename: K
authors.initials: K
authors.lastname: Kawasaki
authors.forename: T
authors.initials: T
authors.lastname: Taguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: K
authors.initials: K
authors.lastname: Shimokawa
mesh_terms: D000700:Analgesics; D000818:Animals; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009019:Morphinans / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives*; D009292:Narcotic Antagonists / Q000494:pharmacology; D011957:Receptors, Opioid / Q000187:drug effects*
chemical_list: D000700:Analgesics; D007211:Indoles; D009019:Morphinans; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D009270:Naloxone; D004743:Enkephalin, Leucine; D009271:Naltrexone; C055382:naltrindole