ANALGESIC POTENCY OF S-ACETYLTHIORPHAN AFTER INTRAVENOUS ADMINISTRATION TO MICE

As hydrolysis in serum of acetorphan to acetylthiorphan (N-[(R,S)-3-acetylmercapto-2-benzylpropanoyl]glycine) has been evidenced, both the neutral endopeptidase inhibition in vitro by acetylthiorphan and analgesic potency of acetylthiorphan after intravenous administration to mice in two analgesic models, the hot-plate and the tail-flick tests, were compared with those of thiorphan and acetorphan. Acetylthiorphan showed a decreased degree of neutral endopeptidase inhibition (IC50 = 316 +/- 38 nM) compared to thiorphan (IC50 = 1.8 +/- 0.2 nM). After intravenous administration followed by the hot-plate jump latency test, acetylthiorphan elicited a degree of analgesia equivalent to that with acetorphan but longer lasting. Like acetorphan and thiorphan, acetylthiorphan was devoid of analgesic activity in the tail-flick test. The results indicated that S-acetylation of the thiol function in acetylthiorphan ensures sufficient lipophilicity to permit crossing of the blood-brain barrier and that acetylthiorphan acts via a prodrug mechanism.