Local Anesthetics: Synthesis, Structural and Physico-Chemical Properties, and Interaction with Model and Biological Membranes

• Grant number: 96/01451-9
• Support Opportunities: Research Projects - Thematic Grants
• Start date: January 01, 1997
• End date: January 31, 2003
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Shirley Schreier
• Grantee: Shirley Schreier
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant(s): 00/07625-6 - 3d-qsar analysis of nitrofuran derivates with antebacterial activity., AR.EXT; 98/07923-5 - Structure activity relationships of nitrofuran derivatives with antibacterial activity., AR.EXT; 98/06207-4 - Solution and membrane-bound conformation of extracellular and cytosolic loops of a g protein coupled receptor., AR.EXT; 98/00344-0 - Hugo Rubén Arias | CONICET - Argentina, AV.EXT; 97/02069-3 - 1H-NMR Relaxation times studies in membrane: anesthetic systems, AR.BR

Abstract

Local anesthetics (LA) act by blocking the action potential as a consequence of their binding to the sodium channel present in nerve cells. Most LA are aminoesters or aminoamides and carry amino groups that undergo ionization equilibria in the physiological pH range. Few of them, such as benzocaine, do not bear ionizable groups. It has been proposed that the mechanism of action of LA involves the uncharged form crossing the membrane lipid bilayer, reestablishment of the ionization equilibrium in the cytosol and binding of the charged form to the sodium channel, leading to the blockage of ion transport. Thus, the interaction with the lipid bilayer represents one of the steps in the mechanism of action of LA. In addition, toxic effects have been also related to LA binding to the lipid bilayer. It is well known that the more hydrophobic, the more effective and the more toxic the LA. The present project proposes: 1-synthesis of compounds with anesthetic activity, as predicted by calculation of structure-activity relationships (GSAR); 2-determination of physico-chemical parameters of these compounds and of conventional LA: ionization constants and rates of hydrolysis (in the presence and absence of membranes); membrane-water partition coefficients; 3-study of the effect of water structure on LA solubility and partitioning into membranes; 4-study of the effect of LA on structural and dynamical properties of membranes by spectroscopic techniques: fluorescence, spin labeling, NMR; 5-study of biological activity: comparison of the effect of homologous series of al on the action potential. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

LEONARDO FERNANDES FRACETO; ENEIDA DE PAULA. Anestésicos locais: interação com membranas de eritrócitos de sangue humano, estudada por ressonância magnética nuclear de ¹H e 31P. Química Nova, v. 27, n. 1, p. 66-71, 2004-02-00. (96/01451-9)

RIOLI, VANESSA; GOZZO, FABIO C.; HEIMANN, ANDREA S.; LINARDI, ALESSANDRA; KRIEGER, JOSÉ E.; SHIDA, CLÁUDIO S.; ALMEIDA, PAULO C.; HYSLOP, STEPHEN; EBERLIN, MARCOS N.; FERRO, EMER S.. Novel natural peptide substrates for endopeptidase 24.15, neurolysin and angiotensin-converting enzyme. Journal of Biological Chemistry, v. 278, n. 10, p. 8547-8555, Mar. 2003. (96/01451-9, 00/11176-2)