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.
Lambert
D M
DM
Laboratory of Medicinal Chemistry, School of Pharmacy, Catholic University of Louvain, Brussels, Belgium.
Mergen
F
F
Poupaert
J H
JH
Dumont
P
P
D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D015260:Neprilysin / Q000037:antagonists & inhibitors; D010147:Pain Measurement / Q000187:drug effects; D015244:Thiorphan / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D000700:Analgesics; C085130:S-acetylthiorphan; D009270:Naloxone; C049331:racecadotril; D015244:Thiorphan; D015260:Neprilysin