Dopamine D3 Receptor Antagonists as Potential Therapeutics for the Treatment of Neurological Diseases

Abstract

D3 receptors represent a major focus of current drug design and development of therapeutics for dopamine-related pathological states. Their close homology with the D2 receptor subtype makes the development of D3 selective antagonists a challenging task. In this review, we explore the relevance and therapeutic utility of D3 antagonists or partial agonists endowed with multireceptor affinity profile in the field of central nervous system disorders such as schizophrenia and drug abuse. In fact, the peculiar distribution and low brain abundance of D3 receptors make them a valuable target for the development of drugs devoid of motor side effects classically elicited by D2 antagonists. Recent research efforts were devoted to the conception of chemical templates possibly endowed with a multi-target profile, especially with regards to other G-protein-coupled receptors (GPCRs). A comprehensive overview of the recent literature in the field is herein provided. In particular, the evolution of the chemical templates has been tracked, according to the growing advancements in both the structural information and the refinement of the key pharmacophoric elements. The receptor/multireceptor affinity and functional profiles for the examined compounds have been covered, together with their most significant pharmacological applications.

Keywords: GPCR; dopamine; drug optimization; multi-targeting approach; receptor antagonists; selectivity.

Figure 1

(A) Alignment between D1 receptor (as an example of D1-like family) and D3 receptor (as an example of D2-like family) as found by PRALINE (http://www.ibi.vu.nl/programs/pralinewww/), non-conserved residues are highlighted by dark blue background. (B) Snake plot representation of the above-mentioned receptors with the non-conserved residues in green for D1 receptor and in orange for D3 receptor. Plots were generated by means of GPCRdb web-server (http://gpcrdb.org/).

Figure 2

Pharmacophore model for D3 selective ligands.

Figure 3

Early identified D3 selective ligands.

Figure 4

Arylpiperazine-based derivatives 5-10.

Figure 5

Arylpiperazine-based derivatives 11-15.

Figure 6

Pyrimidinylpiperazine-based compounds 16–19.

Figure 7

Deconstruction studies performed on D3 receptor ligands 6a and 20.

Figure 8

Schematic representation of the flexible arylpiperazinecarboxamides binding the OBS and SBP of the D3 receptor.

Figure 9

Arylpiperazine-based D3 “dimeric” and bitopic ligands 28 and 29.

Figure 10

Tranylcypromine (30) and Tranylcypromine-based analog 31.

Figure 11

Compounds 32 and 33 and structurally related triazole-based D3 antagonists 34–36.

Figure 12

Representation of the novel pharmacophoric model proposed by Micheli et al. (Bonanomi et al., ; Micheli et al., 2010b), with compound 35 and its features.

Figure 13

Morpholino/triazole analogs 37a–c.

Figure 14

General structure of octahydropyrrolo[2,3-b]pyrrole-based D3 antagonists 38 and 39.