Quantitative structure-activity relationships for N-[(N',N'-disubstituted-amino)acetyl]arylamines for local anesthetic activity and acute toxicity

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Abstract
The synthesis and physicochemical properties of a series of N-[(N'', N''-disubstituted-amino)acetyl]arylamines are described. A QSAR [quantitative structure activity relationship] method is applied to local anesthetic activity and acute toxicity by a nonclassic substituent variation involving a modification on both aryl and amino moieties in mice and rabbits. The choice of the different parameters (partition coefficient, pKa [negative log of the Ka], connectivity index, molar refraction and molar volume) is discussed and their different methods of determination are described. Molar refraction (MR) is the parameter which explains best the variance of the local anesthetic activity, and the quadratic regression with MR leads to a posteriori synthesis of 1 compound with optimized activity. The partition coefficient is the most explicative parameter for i.v. toxicity.

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