Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

Abstract

Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong to two major subfamilies such as D1-like (i.e., D1 and D5 receptors) and D2-like (i.e., D2, D3 and D4) receptors. Dopamine D3 receptor (D3R) was cloned 30 years ago, and its distribution in the CNS and in the periphery, molecular structure, cellular signaling mechanisms have been largely explored. Involvement of D3Rs has been recognized in several CNS functions such as movement control, cognition, learning, reward, emotional regulation and social behavior. D3Rs have become a promising target of drug research and great efforts have been made to obtain high affinity ligands (selective agonists, partial agonists and antagonists) in order to elucidate D3R functions. There has been a strong drive behind the efforts to find drug-like compounds with high affinity and selectivity and various functionality for D3Rs in the hope that they would have potential treatment options in CNS diseases such as schizophrenia, drug abuse, Parkinson's disease, depression, and restless leg syndrome. In this review, we provide an overview and update of the major aspects of research related to D3Rs: distribution in the CNS and periphery, signaling and molecular properties, the status of ligands available for D3R research (agonists, antagonists and partial agonists), behavioral functions of D3Rs, the role in neural networks, and we provide a summary on how the D3R-related drug research has been translated to human therapy.

Keywords: D3 ligands; dopamine D3 functions; dopamine D3 receptor; localization; molecular structure; signalization; therapeutic indications.

Figure 1

(A) D2Rs (blue circles) and D3Rs (red triangles) show distinct distribution within the rat brain (schematic drawing of the median sagittal section of a rat brain modified from the original image created by Gill Brown (source: neuroscience-graphicdesign.com, license: CC BY-NC 4.0). (B) [³H](+)PHNO binding in rat brain coronal section in the absence Gpp(NH)p visualizes both D2Rs and D3Rs. (C) [³H](+)PHNO binding in rat brain coronal section in the presence of 100 µM Gpp(NH)p allows visualization of only D3Rs. Arrows indicate the islands of Calleja, an area in the olfactory tubercle rich in D3Rs. The remaining binding dorsally to the islands of Calleja in the nucleus accumbens indicates high abundance of D3Rs in this area. Autoradiograms by F. Horti and B. Kiss (unpublished).

Figure 2

Structure of the hD3R, which contains the natural ligand (DA) docked into the crystal structure of D3R (ID is 3PBL in the Protein Data Bank; https://www.rcsb.org/).

Figure 3

The D3R antagonist GSK-598809 and the general pharmacophore of D3R selective ligands.