Abstract
The aromatic ring of the antagonist of the dopaminergic receptor behaves as an electron acceptor within its interactions with the receptor. The energy of the lower unoccupied molecular orbital ( ϵ LUMO ) is correlated with the biological activity for different series of neuroleptic compounds. The principle of interaction LUMO antagonist—HOMO receptor (Principle La—Hr), presented previously for the phenothiazine series, is extended to various series of antagonists of the dopaminergic receptor: thioxanthenes, butyrophenones, benzisoxazoles and benzamides. The Principle La—Hr is refined on a model series of 16 phenothiazines by a multilinear regression giving the biological activity versus 3 variables, with a stepwise procedure. The variable ϵ LUMO has the strongest contribution, the aliphatic amine chain has a moderate contribution and the variation of lipophilicity induced by the substituent of the aromatic ring in position 2 has only a very weak contribution. The correlation is used to predict, with success, the relative activity of two new phenothiazines: mesoridazine and thioridazine.
Published Version
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