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 (Imax) 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 (Imax) values of the antagonists as target values. The statistical results for the generated MLR model were: r2 = 0.89, rmsd = 9.01, q2 = 0.83 and loormsd = 11.1; the statistical results for the generated NN model were: r2 = 0.89, rmsd = 8.98, q2 = 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.

Nicotinic Receptor Antagonists as Treatments for Nicotine Abuse

“…The application of this ANN QSAR model has led to the successful discovery of six new compounds in this study and continues to be utilized as a useful predictive tool for our drug discovery efforts. We were also able to develop a QSAR model to predict maximal inhibition ( I max ) values for quaternary ammonium antagonists interacting at α6β2* nAChRs (Zheng, McConell, Zhan, Dwoskin, & Crooks, 2009; Zheng, Zheng, et al, 2009). This represented the first reported QSAR study to predict I max values.…”

Wide-Antimicrobial Spectrum of Picolinium Salts

“…For instance, N -( n -hexadecyl)- and N -( n -heptadecyl)-3-methylpyridinium bromide or 1-methyl-3-octylpyridinium alkyl sulfate were found to be effective for micelle-based drug delivery to improve drug solubility and the bioavailability of anionic drugs and metal complexes [ 28 , 43 ]. The Crooks’ group systematically investigated mono- and bis-picolinium derivatives as promising antagonists of neuronal nicotinic acetylcholine receptors, mediating nicotine-evoked dopamine release [ 45 , 46 , 47 , 48 , 49 ]. Although the antimicrobial activities of quaternary ammonium salts are generally known, the published results regarding the antimicrobial activities of picolinium salts are inconsistent.…”