QSAR study on maximal inhibition (Imax) of quaternary ammonium antagonists for S-(-)-nicotine-evoked dopamine release from dopaminergic nerve terminals in rat striatum

Abstract

Maximal inhibition (I(max)) of the agonist effect is an important pharmacological property of inhibitors that interact with multiple receptor subtypes that are activated by the same agonist and which elicit the same functional response. This report represents the first QSAR study on a set of 66 mono- and bis-quaternary ammonium salts that act as antagonists at neuronal nicotinic acetylcholine receptors mediating nicotine-evoked dopamine release, conducted using multi-linear regression (MLR) and neural network (NN) analysis with the maximal inhibition (I(max)) values of the antagonists as target values. The statistical results for the generated MLR model were: r(2)=0.89, rmsd=9.01, q(2)=0.83 and loormsd=11.1; the statistical results for the generated NN model were: r(2)=0.89, rmsd=8.98, q(2)=0.83 and loormsd=11.2. The maximal inhibition values of the compounds exhibited a good correlation with the predictions made by the QSAR models developed, which provide a basis for rationalizing selection of compounds for synthesis in the discovery of effective and selective second generation inhibitors of nAChRs mediating nicotine-evoked dopamine release.

Figure 1

The calculated versus the experimentally determined I_max values from the DA release assay for the trained (shown in blue squares) and leave-one-out cross-validation (shown in red triangles) for the best MLR QSAR model. The solid line represents a perfect correlation. The dotted lines represent ±20% difference from a perfect fit.

Figure 2

The training and leave-one-out errors (rmsd and loormsd) as functions of the number of training cycles of the NN11-1-1, NN11-2-1 and NN11-3-1 models.

Figure 3

The calculated versus the experimentally determined I_max values from the DA release assay for the trained (shown in blue squares) and leave-one-out cross-validation (shown in red triangles) for the NN11-1-1 QSAR model. The solid line represents a perfect correlation. The dotted lines represent ±20% difference from a perfect fit.