Charge-transfer interactions in the inhibition of MAO-A by phenylisopropylamines--a QSAR study.
The HOMO energies and the charges on the aromatic carbons of two sets of MAO-A-inhibiting phenylisopropylamines, one containing 4-amino substituents, were calculated by the AM1 method, in order to evaluate the importance of charge-transfer interactions between drug and enzyme. Multiple-linear regressions of the pIC50 values on the calculated descriptors were performed with 33 compounds from the two sets, and separately with each set. A poor correlation was obtained when the two sets were merged, as a result of opposing trends shown by the two separate sets. These opposing trends were reconciled by invoking a partial protonation of the basic 4-amino substituents by a hydrogen-bond-donor fragment of the enzyme. The resulting analysis indicated that electron-rich rings and higher HOMO levels tended to increase activity. This model received support from the evaluation of the IMAO activity of four new phenylisopropylamines.
Vallejos
Gabriel
G
Facultad de Química v Biología, Universidad de Santiago, Chile.
Rezende
Marcos Caroli
MC
Cassels
Bruce K
BK
D000662:Amphetamines / Q000737:chemistry / Q000494:pharmacology; D000814:Aniline Compounds / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000201:enzymology; D003198:Computer Simulation; D004579:Electron Transport; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011522:Protons; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D013816:Thermodynamics
D000662:Amphetamines; D000814:Aniline Compounds; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D011522:Protons; D008995:Monoamine Oxidase