Dopamine Transporter Ligands: Recent Developments and Therapeutic Potential

Abstract

The dopamine transporter (DAT) is a target for the development of pharmacotherapies for a number of central disorders including Parkinson's disease, Alzheimer's disease, schizophrenia, Tourette's syndrome, Lesch-Nyhan disease, attention deficit hyperactivity disorder (ADHD), obesity, depression, and stimulant abuse as well as normal aging. Considerable effort continues to be devoted to the development of new ligands for the DAT. In this review, we present some of the more interesting ligands developed during the last few years from the 3-phenytropane, 1,4-dialkylpiperazine, phenylpiperidine, and benztropine classes of DAT uptake inhibitors as well as a few less studied miscellaneous DAT uptake inhibitors. Studies related to the therapeutic potential of some of the more studied compounds are presented. A few of the compounds have been studied as pharmacotherapies for Parkinson's disease, ADHD, and obesity. However, most of the drug discovery studies have been directed toward pharmacotherapies for stimulant abuse (mainly cocaine). A number of the compounds showed decreased cocaine maintained responding in rhesus monkeys trained to self-administer cocaine. One compound, GBR 12,909, was evaluated in a Phase 1 clinical trial.

Dopamine transporter endocytic determinants: Carboxy terminal residues critical for basal and PKC-stimulated internalization

“…DA signaling is implicated in schizophrenia, Parkinson's disease and attention deficit hyperactivity disorder, and treatments targeting these disorders modulate dopaminergic neurotransmission (De Oliveira and Juruena, 2006;Runyon and Carroll, 2006;Carlsson et al, 2007). Extracellular DA levels are regulated by the plasma membrane DAT, which removes DA from the synaptic cleft thereby temporally and spatially constraining DA availability.…”

Synthesis and monoamine transporter binding properties of 2β-[3′-(substituted benzyl)isoxazol-5-yl]- and 2β-[3′-methyl-4′-(substituted phenyl)isoxazol-5-yl]-3β-(substituted phenyl)tropanes

“…Although the DAT tolerates ligands having a broad variety of 2β-substituents with little change in the affinity of the ligand, the nature of the substituents has a profound effect on the monoamine transporter selectivity. 16 To obtain analogs with increased metabolic stability, we have replaced the metabolically labile 2β-ester group of the 3β-phenyltropanes by stable bioisosteric heterocyclic groups, which led to several analogs with high-affinity and selectivity for the DAT. 20,24,30,31 Computational analyses of the electrostatic (molecular electrostatic potential), hydrophobic (calculated logP), and steric (substituted volume) properties of these 2β-heterocyclic analogs strongly suggested electrostatic interactions predominately contributed to their DAT binding affinities.…”

“…11-19 A large part of our structure-activity relationships (SAR) studies was directed towards modification of the 4'-chloro and 4'-methyl analogs 1c,d. 16 Over the last several years, we have synthesized a large number of 3-phenyltropane analogs and evaluated them for binding at monoamine transporters. We have shown that a variety of 2β-esters, amides, and heterocyclic groups possessing either a 4'-chloro or 4'-methylphenyl group at the 3β-position had high-affinity for the DAT, in some cases, with considerably reduced affinity at the NET and 5-HTT.…”

“…We have shown that a variety of 2β-esters, amides, and heterocyclic groups possessing either a 4'-chloro or 4'-methylphenyl group at the 3β-position had high-affinity for the DAT, in some cases, with considerably reduced affinity at the NET and 5-HTT. 16 One of the more interesting classes of compounds in the heterocyclic series is the 2β-[3'-(substituted phenyl)isoxazol-5-yl]-3β-(substituted phenyl)tropanes (2a-h). 20 The DAT selective inhibitor RTI-336 (2e) is currently in advanced preclinical development.…”

Synthesis and receptor binding properties of 2β-alkynyl and 2β-(1,2,3-triazol)substituted 3β-(substituted phenyl)tropane derivatives

“…12, 15-18 One of the most studied classes of DAT inhibitors is the 3-phenyltropanes. 12,15,19,20 The lead compound was 3β-phenyltropane-2β-carboxylic acid methyl ester (2a, Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript.…”