Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter

Abstract

Background Treatment of Stimulant-Use Disorders remains a formidable challenge, and the dopamine transporter (DAT) remains a potential target for antagonist or agonist-like substitution therapies. Methods This review focuses on DAT ligands, such as benztropine, GBR 12909, modafinil, and DAT substrates derived from phenethylamine or cathinone that have atypical DAT-inhibitor effects, either in vitro or in vivo. The compounds are described from a molecular mechanistic, behavioral, and medicinal-chemical perspective. Results Possible mechanisms for atypicality at the molecular level can be deduced from the conformational cycle for substrate translocation. For each conformation, a crystal structure of a bacterial homolog is available, with a possible role of cholesterol, which is also present in the crystal of drosophila DAT. Although there is a direct relationship between behavioral potencies of most DAT inhibitors and their DAT affinities, a number of compounds bind to the DAT and inhibit dopamine uptake but do not share cocaine-like effects. Such atypical behavior, depending on the compound, may be related to slow DAT association, combined sigma-receptor actions, or bias for cytosol-facing DAT. Some structures are sterically small enough to serve as DAT substrates but large enough to also inhibit transport. Such compounds may display partial DA releasing effects, and may be combined with release or uptake inhibition at other monoamine transporters. Conclusions Mechanisms of atypical DAT inhibitors may serve as targets for the development of treatments for stimulant abuse. These mechanisms are novel and their further exploration may produce compounds with unique therapeutic potential as treatments for stimulant abuse.

2-Substituted 3 -Aryltropane Cocaine Analogs Produce Atypical Effects without Inducing Inward-Facing Dopamine Transporter Conformations

“…The correlation among those effects is greater than that for behavioral effects and affinities at the other monoamine transporters (Ritz et al, 1987), suggesting that behavioral effects of cocaine-like drugs are attributable to actions at the DAT (Kuhar et al, 1991). However, an increasing number of DAT inhibitors are being found with effects different from those of cocaine (Reith et al, 2015).…”

“…Contrary to the DAT hypothesis, several groups of compounds with DAT affinity have in vivo or in vitro effects that are distinct from those of standard DAT inhibitors such as cocaine (reviewed by Reith et al, 2015). These "atypical" DAT inhibitors include benztropine (BZT) and its analogs, which consist of the tropane ring of cocaine and the diphenylether moiety common to the piperazine class of DA uptake inhibitors such as GBR 12909 (Van der Zee et al, 1980).…”

“…However, several studies have suggested that antagonist actions at M 1 sites contribute minimally if at all to the atypical effects of BZT analogs (see review by Reith et al, 2015). More recently, it has been suggested that compounds with sigma receptor (sR) antagonist effects along with their affinity for the DAT will exhibit atypical DAT inhibitory effects similar to BZT .…”

“…Another potential mechanism for atypical actions of DAT inhibitors is the stabilization of cytosol-facing conformations resulting from ligand binding (see review by Reith et al, 2015). For example, Loland et al (2008) proposed a correlation between conformational states stabilized with DAT binding and the behavioral effects of a diverse group of DAT ligands.…”

CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction

“…Given that cocaine self-administration behavior is sensitive to fast changes in extracellular DA, the slow-onset long-lasting increase in DA produced by CTDP-32476 may underlie the reduction in cocaine self-administration observed in the present study. Another possibility is that CTDP-32476 may act as other atypical DAT inhibitors such as GBR-12909, benztropine, or modafinil-that induce a 'closed' or inwardfacing conformation upon binding to the DAT (Loland et al, 2008;Reith et al, 2015). Because cocaine has higher binding affinity for the more 'open' conformation, a compound inducing a 'closed' conformation would be more likely to attenuate cocaine binding to the DAT and thus be less effective as a DAT inhibitor.…”