Some pharmacological properties of a newly synthesized morphine derivative, (-)-6 beta-acetylthiomorphine (AcS-morphine) were studied. AcS-morphine was about twice as potent as morphine in the inhibitory action of the twitch response of the guinea-pig ileal preparation to electrical stimulation. AcS-morphine, however, was 5 times as potent as morphine in the analgesic action in the rats. Both the effects of AcS-morphine were inhibited by naloxone, suggesting that the site of action of AcS-morphine is mu-receptors. It is interesting that 6 beta-isomer of AcS-morphine is 5 times as potent as 6 alpha-OH isomer of morphine in the analgesic action, because 6 alpha-OH isomer of morphine is much more potent than that of 6 beta-OH isomer. The effects of AcS-morphine on the specific binding of [3H]-naloxone, [3H]-ethylketocyclazocine and [3H]-D-Ala2-D-Leu5-enkephalin to the membrane fractions from the rat brain were tested. AcS-morphine was about 5 times as potent as morphine in its interactions with opioid receptors, as determined by the binding assay. AcS-morphine, as well as morphine, had a selectively high affinity to mu-receptors. The "sodium effect" and the "GTP effect" of AcS-morphine were almost the same as those of morphine. The dependence liability of AcS-morphine was preliminary tested in the guinea-pig ileal preparations treated with a high concentration of AcS-morphine for 24 hr. Results suggested that AcS-morphine is weaker than morphine in its dependence liability, though it seems almost certain that AcS-morphine does have this liability.

Analgesics↗

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Some pharmacological properties of a newly synthesized 3-acetoxy-6 beta-acetylthio-10-oxo-N-cyclopropylmethyl-dihydronormorphine (KT-95).

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.

Analgesia↗