Recent findings leading to the discovery of selective dopamine D4 receptor ligands for the treatment of widespread diseases

Abstract

Since its discovery, the dopamine D₄ receptor (D₄R) has been suggested to be an attractive target for the treatment of neuropsychiatric diseases. Novel findings have renewed the interest in such a receptor as an emerging target for the management of different diseases, including cancer, Parkinson's disease, alcohol or substance use disorders, eating disorders, erectile dysfunction and cognitive deficits. The recently resolved crystal structures of D₄R in complexes with the potent ligands nemonapride and L-745870 strongly improved the knowledge on the molecular mechanisms involving the D₄R functions and may help medicinal chemists in drug design. This review is focused on the recent development of the subtype selective D₄R ligands belonging to classical or new chemotypes. Moreover, ligands showing functional selectivity toward G protein activation or β-arrestin recruitment and the effects of selective D₄R ligands on the above-mentioned diseases are discussed.

Keywords: Chemotypes; Crystal structures; D(4) receptor agonists and antagonists; Dopamine D(4) receptor; Structure-activity relationships; Therapeutic potential of D(4) receptor ligands.