title: Synthesis and pharmacological properties of 2-[S-acetylthiorphan]-1,3- diacylaminopropan-2-ol derivatives as chimeric lipid drug carriers containing an enkephalinase inhibitor.
abstract: The design of 1,3-dacylaminopropan-2-ols as CNS-directed carrier groups is based on their resemblance to endogenous lipids and the properties of pseudotriglyceride esters to facilitate the brain penetration of therapeutic agents. 2-[S-acetylthiorphan]-1,3-diacylaminopropan-2-ols, differing from the nature of 1,3-acyl chains, were synthesized and evaluated in vivo using the hot-plate jump test. The compounds exhibited naloxone reversible analgesic properties. The effects were superior to those of parent compounds thiorphan and S-acetylthiorphan. The palmitoyl derivative showed also activity at 0.8 mmol/kg after oral administration. Like acetorphan, a thiorphan prodrug, these compounds were poor substrates for brain enkephalinase, suggesting the release of the pharmacological active inhibitor at the site of action in the brain.
authors.affiliation: Laboratory of Medicinal Chemistry, School of Pharmacy, Catholic University of Louvain, Brussels, Belgium.
authors.forename: D M
authors.initials: DM
authors.lastname: Lambert
authors.forename: F
authors.initials: F
authors.lastname: Mergen
authors.forename: C F
authors.initials: CF
authors.lastname: Berens
authors.forename: J H
authors.initials: JH
authors.lastname: Poupaert
authors.forename: P
authors.initials: P
authors.lastname: Dumont
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D004337:Drug Carriers; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010147:Pain Measurement / Q000187:drug effects; D015244:Thiorphan / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000700:Analgesics; D004337:Drug Carriers; D009270:Naloxone; D015244:Thiorphan; D015260:Neprilysin