Enhancement of drug affinity for cell membranes by conjugation with lipoamino acids II. Experimental and computational evidence using biomembrane models.
Lipoamino acids (LAAs) are promoieties able to enhance the amphiphilicity of drugs, facilitating their interaction with cell membranes. Experimental and computational studies were carried out on two series of lipophilic amide conjugates between a model drug (tranylcypromine, TCP) and LAA or alkanoic acids containing a short, medium or long alkyl side chain (C-4 to C-16). The effects of these compounds were evaluated by monolayer surface tension analysis and differential scanning calorimetry using dimyristoylphosphatidylcholine monolayers and liposomes as biomembrane models. The experimental results were related to independent calculations to determine partition coefficient and blood-brain partitioning. The comparison of TCP-LAA conjugates with the related series of TCP alkanoyl amides confirmed that the ability to interact with the biomembrane models is not due to the mere increase of lipophilicity, but mainly to the amphipatic nature and the kind of LAA residue.
Pignatello
Rosario
R
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Catania, Viale A. Doria, 6, I-95125 Catania, Italy. r.pignatello@unict.it
Guccione
Salvatore
S
Castelli
Francesco
F
Sarpietro
Maria G
MG
Giurato
Laura
L
Lombardo
Massimo
M
Puglisi
Giovanni
G
Toth
Istvan
I
D000596:Amino Acids / Q000737:chemistry* / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004134:Dimyristoylphosphatidylcholine / Q000378:metabolism; D007700:Kinetics; D008081:Liposomes / Q000378:metabolism; D008954:Models, Biological; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011312:Pressure; D012995:Solubility; D013329:Structure-Activity Relationship; D013501:Surface-Active Agents / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics; D014191:Tranylcypromine / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
D000596:Amino Acids; D008081:Liposomes; D008996:Monoamine Oxidase Inhibitors; D013501:Surface-Active Agents; D014191:Tranylcypromine; D004134:Dimyristoylphosphatidylcholine