title: 1,3-Diacylaminopropan-2-ols and corresponding 2-acyl derivatives as drug carriers: unexpected pharmacological properties.
abstract: The design of lipid vectors (pseudotriglycerides, PTGs), achieved by the amide isosteric substitution of the ester moieties of 1,3-diacylglycerols, is based on the structural similarity with natural triglycerides facilitating the passage of pharmacological agents across biological membranes. 2-S-Acetylthiorphan (hemiacetorphan) pseudotriglycerides, Z-glycine pseudotriglycerides and 1,3-diacylaminopropan-2-ols vector molecules differing by the nature of the acid side-chain are examined in acute toxicity, radioligand binding and guinea-pig ileum experiments. These evaluations have led us to distinguish two types of compounds. Linear derivatives, palmitoyl and decanoyl, are devoid of toxicity and intrinsic activity. Cyclic derivatives, which contain in the acyl chain a phenyl, cyclohexyl, cyclopentyl or adamantoyl ring, present additional properties. Cyclic derivatives of hemiacetorphan are lethal after intravenous administration. The mortality is governed by the 2-hemiacetorphan moiety in the cyclic vector molecules. Hemiacetorphan alone is also lethal. Cyclic vector molecules and related compounds inhibit the contractile response of the guinea-pig ileum induced by electrical stimulation, histamine or acetylcholine (noncompetitive antagonism) whereas linear entities and parent compounds are not active. In particular, the 2-hemiacetorphan 1,3-diadamantoylamide PTG presents pD'2 values 7.87 +/- 0.29 (vs histamine) and 7.97 +/- 0.12 (vs acetylcholine).
authors.affiliation: School of Pharmacy, Laboratory of Medicinal Chemistry, Catholic University of Louvain, Brussels, Belgium.
authors.forename: D M
authors.initials: DM
authors.lastname: Lambert
authors.forename: L
authors.initials: L
authors.lastname: Neuvens
authors.forename: F
authors.initials: F
authors.lastname: Mergen
authors.forename: B
authors.initials: B
authors.lastname: Gallez
authors.forename: J H
authors.initials: JH
authors.lastname: Poupaert
authors.forename: J
authors.initials: J
authors.lastname: Ghysel-Burton
authors.forename: J M
authors.initials: JM
authors.lastname: Maloteaux
authors.forename: P
authors.initials: P
authors.lastname: Dumont
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism; D004337:Drug Carriers / Q000138:chemical synthesis*; D004558:Electric Stimulation; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010277:Parasympathomimetics / Q000494:pharmacology; D011412:Propanolamines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004337:Drug Carriers; D010277:Parasympathomimetics; D011412:Propanolamines; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D017480:Receptors, sigma; D006632:Histamine