Synthesis and pharmacological properties of 2-[S-acetylthiorphan]-1,3- diacylaminopropan-2-ol derivatives as chimeric lipid drug carriers containing an enkephalinase inhibitor.

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.