Recent Advances in the Development of Dopamine D₃Receptor Antagonists: a Medicinal Chemistry Perspective

Abstract

Dopamine (DA) D(3) receptor antagonism might play a significant role in different therapeutic areas. A high number of preclinical studies on DA D(3) receptor antagonists have shown efficacy in animal models of Parkinson's disease, schizophrenia and drug dependence. This Review covers the activities of medicinal chemists in this field over the last ten years towards the identification of truly selective compounds. Both primary and patent literature is reviewed here. Since the original discoveries, a clear trend towards the optimization of the developability properties of the new scaffold has clearly emerged with time, from both academic and industrial researchers. Examples of advanced leads from academia and industry are described. The latest potential therapeutic applications are reported too.

Using click chemistry toward novel 1,2,3-triazole-linked dopamine D3 receptor ligands

“…22 Indeed, triazole ureas have been designed to inhibit hydrolases. 23 It should be noted that others have recently investigated the 1,2,3-triazole template for novel D3R ligands, 24,25 and the 1,2,4-triazole motif has also provided a rich set of D3R-selective antagonists, 26,27 exemplified by the clinically investigated GSK598,809. 9,28 …”

Applying a multitarget rational drug design strategy: the first set of modulators with potent and balanced activity toward dopamine D3 receptor and fatty acid amide hydrolase

“…In Figure 1, examples of known D3 selective modulators ( 1-3 ) 5 and FAAH inhibitors ( 4-6 ) 9 are reported. We realized that it was possible to devise a dual-target pharmacophore model exploiting the overlap between the pharmacophoric features of DRD3 partial agonists and those of the O -aryl carbamate derivatives (Figure S1 in Supporting Information).…”

“…In this case, the main issue was the selectivity over DRD2, which, dropping from over 150- to 23-fold, was negatively affected by this substitution. Next, considering that: i) 3 is completely devoid of CB 1 activity and that ii) the naphthyl group was already reported on both DRD3 modulators 5 and FAAH inhibitors, 26 the two naphthyl-substituted regioisomers 16 and 17 were synthesized. These compounds were endowed with good and balanced activities in the low nanomolar range.…”

Beyond Small-Molecule SAR

“…Several comprehensive reviews describing dozens of D3-selective agents and derived structure-activity relationships (SAR) have been published recently (Heidbreder & Newman, 2010; Micheli, 2011; Ye et al, 2013). Despite fertile ground for modification of the classic D3 pharmacophore template, several challenges remain in identifying D3-selective ligands with efficacies that can be translated into in vivo models and ultimately therapeutic agents to treat human addiction.…”

“…These properties may also contribute to the need to use higher doses of drug to observe activity in vivo than might have been predicted from their low nanomolar D3 receptor binding affinities. Several examples of these early preclinical candidates have been compared (Heidbreder & Newman, 2010; Micheli, 2011). The early 2-OMe or 2,3-diCl-4-phenylpiperazine fragment has been substituted with many different substituents and even the phenyl ring has been elaborated on with various heteroaryl ring systems.…”