title: Recent advances in the search for D3- and D4-selective drugs: probes, models and candidates.
abstract: 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.
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Löber
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.forename: Nuska
authors.initials: N
authors.lastname: Tschammer
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
mesh_terms: D000818:Animals; D018491:Dopamine Agonists / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D015507:Drugs, Investigational / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000378:metabolism; D050638:Receptors, Dopamine D4 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D018491:Dopamine Agonists; D015507:Drugs, Investigational; D008024:Ligands; D010879:Piperazines; D010880:Piperidines; D050637:Receptors, Dopamine D3; D050638:Receptors, Dopamine D4