Inhibition of Butyrylcholinesterase by Phenothiazine Derivatives |
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Authors: | Jean Debord Louis Merle Jean-Claude Bollinger Thierry Dantoine |
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Institution: | 1. Service de Pharmacologie-Toxicologie, H?pital Dupuytren, 2 Avenue Martin Luther King, 87042 Limoges, France;2. Laboratoire de Pharmacologie, Faculté de Médecine, 2 Rue du Docteur Marcland, 87025 Limoges, France;3. Laboratoire des Sciences de l'Eau et de l'Environnement, Faculté des Sciences, 123 Avenue Albert Thomas, 87060 Limoges, France;4. Service de Médecine Gériatrique, H?pital Dupuytren, 2 Avenue Martin Luther King, 87042 Limoges, France |
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Abstract: | 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 i) were in the range 0.05 to 5 μM. 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 non-polar amino acids. |
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Keywords: | Butyrylcholinesterase Phenothiazine Lipophilicity Molecular Modeling Structure-activity Relationships |
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