title: Lipophilicity as a determinant of binding of procaine analogs to rat α3β4 nicotinic acetylcholine receptor.
abstract: Nicotinic acetylcholine receptors (nAChRs) have been studied in detail with regard to their interaction with therapeutic and drug addiction-related compounds. Using a structure-activity approach, we have examined the relationship among the molecular features of a set of eight para-R-substituted N,N-[(dimethylamino)ethyl] benzoate hydrochlorides, structurally related to procaine and their affinity for the α(3)β(4) nAChR heterologously expressed in KXα3β4R2 cells. Affinity values (log[1/IC50]) of these compounds for the α(3)β(4) nAChR were determined by their competition with [(3)H]TCP binding. Log(1/IC50) values were analyzed considering different hydrophobic and electronic parameters and those related to molar refractivity. These have been experimentally determined or were taken from published literature. In accordance with literature observations, the generated cross-validated quantitative structure-activity relationship (QSAR) equations indicated a significant contribution of hydrophobic term to binding affinity of procaine analogs to the receptor and predicted affinity values for several local anesthetics (LAs) sets taken from the literature. The predicted values by using the QSAR model correlated well with the published values both for neuronal and for electroplaque nAChRs. Our work also reveals the general structure features of LAs that are important for interaction with nAChRs as well as the structural modifications that could be made to enhance binding affinity.
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Arquimedes
authors.initials: A
authors.lastname: Cheffer
authors.forename: Elba Vieira
authors.initials: EV
authors.lastname: Mustafa
authors.forename: Antonia
authors.initials: A
authors.lastname: T-do Amaral
authors.forename: Henning
authors.initials: H
authors.lastname: Ulrich
mesh_terms: D000779:Anesthetics, Local / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D011343:Procaine / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics*; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000779:Anesthetics, Local; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; D011343:Procaine