Recent advances towards the discovery of dopamine receptor ligands

Abstract

Dopamine is a key regulator in the CNS, contributing importantly to functions of arousal and attention, initiation of movement, perception, motivation and emotion. Its imbalance has been implicated in the pathophysiology, and more clearly in the pharmacology, of a number of neurobehavioural disorders, including Parkinson’s disease, schizophrenia, mania and depression, alcohol and drug abuse, as well as attention and eating disorders. Five major dopamine receptor subtypes (D1 – D5) have been identified, with distinct differences in their genes and peptide composition, molecular functions and neuropharmacology. These receptors represent the rational targets for the treatment of a large number of neurological and psychiatric disorders. In recent years, substantial efforts have addressed the most recently described dopamine receptor types, particularly types D3, D4 and D5, although most research involves the longer-known D1 and D2 dopamine receptors. Current pharmacological efforts in medicinal chemistry and neuropharmacology include the development of D1 full agonists and D2 partial agonists, as well as agents with dopaminergic activity combined with effects at CNS serotonergic, muscarinic, adrenergic and histaminic receptors. This review provides an overview of the recent patent literature during 2003 – 2005 on the development of therapeutic agents, mainly targeting the five dopamine receptors.

Keywords::

• atypical antipsychotic
• brain disorder
• CNS
• dopamine
• dopamine agonist
• dopamine antagonist
• dopamine receptor
• Parkinson’s disease
• schizophrenia
• serotonin

Acknowledgement

We thank RJ Baldessarini and JL Neumeyer for their mentorship and profound suggestion during the preparation of this manuscript. We also thank S Ara for her help in search of the patent reference for this manuscript. Work presented in this review was made possible by generous support from the Hundred Talent Project of the Chinese Academy of Sciences (to AZ), and the Adam Corneel Young Investigator Fellowship (to AZ). Support from Shanghai Institute of Materia Medica is also highly acknowledged.