title: A PCILO study of the pharmacologically active conformation of local anesthetics of the procaine type. Conformational analysis and complex formation of protonated 2-diethylaminoethyl-acetate with formate anion.
abstract: To rationalize and improve receptor selectivity of local anesthetics of the procaine type a dynamic two-center model of the pharmacon-receptor interaction is suggested. A quantum chemical study within the Perturbation Configuration Interaction using Localized Orbitals (PCILO) approximations is carried out to find indications for a conformational change of this flexible drug from its thermodynamically preferred conformation to its pharmacologically active one. For this purpose, the pharmacon-receptor interaction is simulated quantum chemically by the interaction of the local anesthetic model compound 2-diethylaminoethyl-acetate (acetylcaine) with the one-center receptor model formate anion and the two-center receptor model gamma-aminobutyric acid in its zwitterionic form. In the present study, the conformational behaviour of acetylcaine is investigated in detail, confirming this molecule to be an appropriate model for procaine. In its formate complex the preferred conformation of acetylcaine is still retained with regard to the torsional angle of the [OCCN] fragment. Artefacts of the in-vacuo condition of the calculation are discussed. In view of the proposed interaction model, the importance of the first interaction of acetylcaine with the anionic receptor site is found to be in the fixation of the local anesthetic at the receptor surface, due to the long-range character of this interaction. Furthermore, an increased polarity of the carbonyl group of acetylcaine due to this interaction may enhance the proposed second interaction with the receptor.
mesh_terms: D000779:Anesthetics, Local / Q000032:analysis*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003201:Computers; D005021:Ethylamines / Q000032:analysis; D005561:Formates / Q000032:analysis; D008968:Molecular Conformation; D011343:Procaine / Q000032:analysis*
chemical_list: D000779:Anesthetics, Local; D005021:Ethylamines; D005561:Formates; C049455:acetylcaine; D011343:Procaine