RT Journal Article
SR Electronic
T1 Pharmacological properties of acetorphan, a parenterally active "enkephalinase" inhibitor.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 937
OP 944
VO 237
IS 3
A1 J M Lecomte
A1 J Costentin
A1 A Vlaiculescu
A1 P Chaillet
A1 H Marcais-Collado
A1 C Llorens-Cortes
A1 M Leboyer
A1 J C Schwartz
YR 1986
UL http://jpet.aspetjournals.org/content/237/3/937.abstract
AB Acetorphan, i.e. N-[(R,S)-3-acetylmercapto-2-benzylpropanoyl]-glycine, benzyl ester, is a lipophilic derivative of Thiorphan, a potent inhibitor of "enkephalinase" (EC 3.4.24.11). On purified enkephalinase its inhibitory potency was approximately 1000 fold less than that of Thiorphan but became close to the latter (nanomolar) when it was incubated previously with cerebral membranes. After parenteral administration to mice and rats (1-10 mg/kg) extensive inhibition of cerebral enkephalinase was shown by the depressed enzyme activity in brain membranes from treated animals and the long-lasting potentiation of analgesia elicited by (D-Ala2,Met5)enkephalin (i.c.v.). This suggests that acetorphan easily enters the brain where the active Thiorphan is released. Parenteral acetorphan elicited a series of naloxone-reversible, opioid-like effects, most of which were described previously with intracerebral Thiorphan or other enkephalinase inhibitors. Antinociceptive effects were found in some tests (hot plate jump and phenylbenzoquinone-induced writhing) but not in others (hot plate licking and tail withdrawal). "Antidepressant" effect was found in the "mouse despair" test and antidiarrhoeal effect in the rat castor oil test. Acetorphan also elicited significant increases and decreases in turnover indexes of serotonin and noradrenaline, respectively, in mouse cerebral cortex. In mice chronically treated with acetorphan, the antinociceptive activity of the compound was not modified markedly and no overt withdrawal symptom could be observed after either treatment interruption or administration of naloxone.