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Theoretical Study on the Local Anaesthetic-Receptor Interaction

M. Remko, K. R. Liedl, and B. M. Rode

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, SK-832 32 Bratislava


Abstract: Theoretical methods are applied to study the local anaesthetics (LAs) procaine, 2-chloroprocaine, tetracaine, benzocaine, DI-MAPA, procainamide, lidocaine, tocainide, mepivacaine, ropivacaine, bupivacaine, etidocaine, 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 aromatic ring, and an additional functional group containing oxygen with lone electron pairs. Based on these ideas a model for the binding of the lidocaine at the transmembrane protein was constructed. Ab initio SCF method was used to study two-component lidocaine receptor binding site composed of formate (Glu-, Asp-) and protonated methylamine (Lys+, Arg+). The binding of LAs to the receptor may be understood by considering a two-step process of recognition and binding of LA to its receptor. Within this model the lidocaine cation is in the first step recognized and bonded at the negatively charged part of the receptor. In a subsequent step the interaction between the amide oxygen and cationic amine group of membrane protein may follow.

Full paper in Portable Document Format: 514a234.pdf


Chemical Papers 51 (4) 234–241 (1997)

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