Inhibition of butyrylcholinesterase by phenothiazine derivatives.
The inhibition of horse serum butyrylcholinesterase (EC 3.1.1.8) by 10 phenothiazine or thioxanthene derivatives was studied with a purified enzyme. Most compounds were mixed inhibitors, but for some of them an apparent competitive inhibition was observed. The competitive inhibition constants (K) were in the range 0.05 to 5 microM. The structures of the inhibitors were modeled by geometry optimization with the AM1 semi-empirical molecular orbital method and octanol/water partition coefficients were estimated with the CLOGP software. Quantitative structure-activity relationships identified lipophilicity, molecular volume, and electronic energies as the main determinants of inhibition. This quantitative model suggested hydrophobic and charge-transfer interactions of the phenothiazine ring with a tryptophan residue at the "anionic" site of the enzyme, and a hydrophobic interaction of the lateral chain with nonpolar amino acids.
Debord
Jean
J
Service de Pharmacologie-Toxicologie, Hĵpital Dupuytren, Limoges, France. debord.jean@wanadoo.fr
Merle
Louis
L
Bollinger
Jean-Claude
JC
Dantoine
Thierry
T
D000818:Animals; D002091:Butyrylcholinesterase / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006736:Horses; D007700:Kinetics; D008958:Models, Molecular; D010640:Phenothiazines / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D013892:Thioxanthenes / Q000737:chemistry / Q000494:pharmacology
D002800:Cholinesterase Inhibitors; D010640:Phenothiazines; D013892:Thioxanthenes; D002091:Butyrylcholinesterase; C031637:phenothiazine