Design, Synthesis and Interaction at the Vesicular Monoamine Transporter-2 of Lobeline Analogs: Potential Pharmacotherapies for the Treatment of Psychostimulant Abuse

Peter      A. Crooks; Guangrong      Zheng; Ashish      P. Vartak; John      P. Culver; Fang      Zheng; David      B. Horton; Linda      P. Dwoskin

Abstract

The vesicular monoamine transporter-2 (VMAT2) is considered as a new target for the development of novel therapeutics to treat psychostimulant abuse. Current information on the structure, function and role of VMAT2 in psychostimulant abuse are presented. Lobeline, the major alkaloidal constituent of Lobelia inflata, interacts with nicotinic receptors and with VMAT2. Numerous studies have shown that lobeline inhibits both the neurochemical and behavioral effects of amphetamine in rodents, and behavioral studies demonstrate that lobeline has potential as a pharmacotherapy for psychostimulant abuse. Systematic structural modification of the lobeline molecule is described with the aim of improving selectivity and affinity for VMAT2 over neuronal nicotinic acetylcholine receptors and other neurotransmitter transporters. This has led to the discovery of more potent and selective ligands for VMAT2. In addition, a computational neural network analysis of the affinity of these lobeline analogs for VMAT2 has been carried out, which provides computational models that have predictive value in the rational design of VMAT2 ligands and is also useful in identifying drug candidates from virtual libraries for subsequent synthesis and evaluation.

Keywords: Vesicular monoamine transporter-2(VMAT2), psychostimulant abuse, lobeline, lobeline analogs, computational modeling, nicotinic receptors, neurochemical and behavioral effects of amphetamine, neuronal nicotinic acetylcholine receptors, rational design, in identifying drug candidates, virtual libraries, subsequent synthesis and evaluation, synaptic storage vesicles, DA transport, reduced drug-seeking behavior