title: Some pharmacological properties of a newly synthesized 3-acetoxy-6 beta-acetylthio-10-oxo-N-cyclopropylmethyl-dihydronormorphine (KT-95).
abstract: The pharmacological properties of a newly synthesized 3-acetoxy-6 beta-acetylthio-10-oxo-N-cyclopropylmethyl-dihydronormorphine (KT-95) were examined. This compound, as well as (-)-3-acetyl-6 beta-acetylthio-N-cyclopropylmethylnormorphine (KT-90) and morphine, inhibited the twitch response to electrical stimulation of the guinea-pig ileal preparation that contains mu- and kappa-receptors. The inhibitory effect of KT-95 was about 17 times more potent than morphine, and about 4 times more potent than KT-90. In the guinea-pig ileal preparation, KT-95 behaved as a mu-antagonist against morphine in the presence of norbinaltorphimine (3 x 10(-8) M). In the rabbit vas deferens, containing kappa-opioid receptors, KT-95 inhibited the twitch response to electrical stimulation in a concentration-dependent manner. Norbinaltorphimine concentration-dependently caused parallel rightward shifts of the concentration-response curves to KT-95 in the guinea-pig ileum and in the rabbit vas deferens after electrical stimulation, suggesting that KT-95 behaved as an agonist for the kappa-opioid receptor. In the mouse vas deferens, that contains delta-receptors. KT-95 behaved also as a delta-antagonist against Leu-enkephalin in the presence of norbinaltorphimine. KT-95, KT-90 and morphine were examined for their potencies in displacing the specific binding of [3H]naloxone (mu-selective ligand), [3H]U69593 (kappa-selective ligand), and [3H]D-Ala2-D-Leu5-enkephalin (delta-selective ligand) to synaptosomal fractions from rat brain. Although KT-95 had a higher nonselective affinity to mu-receptors than KT-90 and morphine, the affinity of KT-95 to kappa-receptors was about 18 times higher than that of morphine, and about 5 times higher than that of KT-90. In the acetic acid-induced writhing test, subcutaneously injected KT-95 was more potent than morphine. Furthermore, the analgesic effect, induced by KT-95 (0.062 mumol/kg, s.c.), was abolished by simultaneous administration of norbinaltorphimine (0.020 mumol/mouse, s.c.), suggesting that the analgesic action of KT-95 is mediated through the kappa-opioid receptor. In the pressure test, KT-95 was 20.17 times more potent than morphine. The analgesic action, induced by KT-95 (2.05 mumol/kg, s.c.), was also in this test abolished by simultaneous administration of norbinaltorphimine (0.14 mumol/rat, s.c.), suggesting that this action of KT-95 is mediated through the kappa-opioid receptor. These results indicate that KT-95 behaves as a kappa-agonist with mu- and delta-antagonistic activities, and suggest that analgesia, induced by KT-95, is mainly mediated through kappa-receptors.
authors.affiliation: Department of Chemical Pharmacology, Toho University School of Pharmaceutical Sciences, Chiba, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Hosoki
authors.forename: S
authors.initials: S
authors.lastname: Niizawa
authors.forename: K
authors.initials: K
authors.lastname: Koike
authors.forename: T
authors.initials: T
authors.lastname: Sagara
authors.forename: K
authors.initials: K
authors.lastname: Kanematsu
authors.forename: I
authors.initials: I
authors.lastname: Takayanagi
mesh_terms: D000698:Analgesia; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D009022:Morphine Derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; 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; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism; D014649:Vas Deferens / Q000187:drug effects* / Q000378:metabolism
chemical_list: C104277:KT 95; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C065295:KT 90; C051844:norbinaltorphimine; D009271:Naltrexone; D009020:Morphine