5-ht5A receptors as a therapeutic target.

Abstract The 5-ht 5A receptor is enigmatic among 5-HT receptors since, although the human receptor was cloned in 1994, until recently, very little has been learnt about the function of the receptor in native tissues. Findings from 5-ht 5A receptor mRNA localisation and immunolabelling studies have revealed widespread expression in the CNS, and have provided pointers to the potential functional role(s) of the receptor. The expression of the 5-ht 5A receptor in raphe nuclei and in higher brain areas, such as the cerebral cortex and hippocampus, suggests a potential autoreceptor function whilst localisation in the suprachiasmatic nucleus (SCN) suggests a role in circadian rhythm control. Additionally, 5-ht 5A receptor knockout mouse phenotyping studies support a role in the control of exploratory behaviour. The lack of understanding of the role of the receptor has been, in part, due to the lack of available selective 5-ht 5A receptor ligands. However, a selective 5-ht 5A receptor antagonist, 3-cyclopentyl- N -[2-(dimethylamino)ethyl]- N -[(4′-{[(2-phenylethyl)amino]methyl}-4-biphenylyl)methyl]propanamide dihydrochloride (SB-699551-A), has recently been identified which appears to be a useful tool with which to elucidate the physiological function of the receptor. Brain localisation and functional studies to date potentially implicate the receptor in the control of circadian rhythms, mood and cognitive function, whilst gene association studies implicate the receptor in the aetiology of schizophrenia. Although much is still to be learnt about the function of the 5-ht 5A receptor, on the basis of these findings, it can be speculated that 5-ht 5A receptor-selective ligands might show utility in psychiatric disorders such as schizophrenia and unipolar depression in which cognitive or mood disturbances are a feature.