Recent advances in the search for D3- and D4-selective drugs: probes, models and candidates

Dopamine D(2)-like receptors (including D(2), D(3) and D(4)) belong to the 'rhodopsin-like' family of G protein-coupled receptors (GPCRs), which represent the largest group of targets for bioactive molecules. Due to their high sequence similarity, the design of subtype-selective ligands requires rational and effective strategies. The general formula of 1,4-disubstituted aromatic piperidines and piperazines (1,4-DAPs) was extracted from classical dopaminergic drugs. The biological properties of this compound family are encoded by an aromatic head group that controls intrinsic activity, an amine moiety and a lipophilic appendage. D(3)- and D(4)-selective molecular probes and drug candidates were generated from the general formula of 1,4-DAP. Formal structural rearrangement led to investigational drugs beyond the 1,4-DAP structure. The very recent publication of the X-ray crystal structure of D(3) should facilitate efficient discovery of unprecedented chemotypes. However, the development of D(3)-selective agonists, functionally selective ligands and the exploitation of homo- and heteromers remain challenging.