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

Trends Pharmacol Sci. 2011 Mar;32(3):148-57. doi: 10.1016/ Epub 2011 Jan 12.


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.

Publication types

  • Review

MeSH terms

  • Animals
  • Dopamine Agonists / chemistry
  • Dopamine Agonists / pharmacology*
  • Drug Design
  • Drugs, Investigational / chemistry
  • Drugs, Investigational / pharmacology
  • Humans
  • Ligands
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Piperidines / chemistry
  • Piperidines / pharmacology
  • Receptors, Dopamine D3 / agonists*
  • Receptors, Dopamine D3 / metabolism
  • Receptors, Dopamine D4 / agonists*
  • Receptors, Dopamine D4 / metabolism
  • Structure-Activity Relationship


  • Dopamine Agonists
  • Drugs, Investigational
  • Ligands
  • Piperazines
  • Piperidines
  • Receptors, Dopamine D3
  • Receptors, Dopamine D4