Dopamine D3 receptor ligands with antagonist properties.

The dopamine D(3) receptor has been recognized to play an important role in the molecular mechanisms of various neuropsychiatric disorders. The development of new dopamine D(3) receptor selective antagonists is premised on the potentially improved therapeutic treatment of psychosis like schizophrenia. Partial agonists at dopamine D(3) receptors are supposed to be beneficial when administered to drug abusers or in Parkinson's disease. The structural basis for most compounds is at least a basic, aryl-substituted alkanamine part with an alkyl moiety, which in many compounds forms a spacer to another aryl residue. Structural variety among the amine moiety includes aminotetralins, tetrahydroisoquinolines, isoindoles, benzazepines, and aminoindans, as well as pyrrolidines, pyrroles, and 4-phenylpiperazines. Various ways for lead optimization are shown in different classes of compounds. Promising ligands with high D(3) receptor affinity often lack sufficient selectivity or display deficits in the required in vivo parameters. Structure-activity relationships for dopamine D(3) receptor antagonists and partial agonists are discussed here, along with the outlook for their potential therapeutic application.