THEORETICAL-STUDY ON THE LOCAL ANESTHETIC-RECEPTOR INTERACTION

Theoretical methods are applied to study the local anaesthetics (LAs) procaine, 2-chloroprocaine, tetracaine, benzocaine, DI-MAPA, procainam ide, lidocaine, tocainide, mepivacaine, ropivacaine, bupivacaine, etid ocaine, W36017, and prilocaine. The AM1 method is used to construct a three-centre pharmacophore model for both ester and amide types of LAs . This model consists of an amine nitrogen atom that is protonated to a higher degree at physiological pH, a flat hydrophobic region of arom atic ring, and an additional functional group containing oxygen with l one electron pairs. Based on these ideas a model for the binding of th e lidocaine at the transmembrane protein was constructed. Ab initio SC F method was used to study two-component lidocaine receptor binding si te composed of formate (Glu(-), Asp(-)) and protonated methylamine (Ly s(+), Arg(+)). The binding of LAs to the receptor may be understood by considering a two-step process of recognition and binding of LA to it s receptor. Within this model the lidocaine cation is in the first ste p recognized and bonded at the negatively charged part of the receptor . In a subsequent step the interaction between the amide oxygen and ca tionic amine group of membrane protein may follow.