SB 699551

SB-699551-A (3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4'-{[(2-phenylethyl)amino]methyl}-4 -biphenylyl)methyl]propanamide dihydrochloride), a novel 5-ht5A receptor-selective antagonist, enhances 5-HT neuronal function: Evidence for an autoreceptor role for the 5-ht5A receptor in guinea pig brain.[Pubmed:16846620]

Neuropharmacology. 2006 Sep;51(3):566-77.

This study utilised the selective 5-ht(5A) receptor antagonist, SB-699551-A (3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4'-{[(2-phenylethyl)amino]methyl}-4 -biphenylyl)methyl]propanamide dihydrochloride), to investigate 5-ht5A receptor function in guinea pig brain. SB-699551-A competitively antagonised 5-HT-stimulated [35S]GTPgammaS binding to membranes from human embryonic kidney (HEK293) cells transiently expressing the guinea pig 5-ht5A receptor (pA2 8.1+/-0.1) and displayed 100-fold selectivity versus the serotonin transporter and those 5-HT receptor subtypes (5-HT(1A/B/D), 5-HT2A/C and 5-HT7) reported to modulate central 5-HT neurotransmission in the guinea pig. In guinea pig dorsal raphe slices, SB-699551-A (1 microM) did not alter neuronal firing per se but attenuated the 5-CT-induced depression in serotonergic neuronal firing in a subpopulation of cells insensitive to the 5-HT1A receptor-selective antagonist WAY-100635 (100 nM). In contrast, SB-699551-A (100 or 300 nM) failed to affect both electrically-evoked 5-HT release and 5-CT-induced inhibition of evoked release measured using fast cyclic voltammetry in vitro. SB-699551-A (0.3, 1 and 3 mg/kg s.c.) did not modulate extracellular levels of 5-HT in the guinea pig frontal cortex in vivo. However, when administered in combination with WAY-100635 (0.3 mg/kg s.c.), SB-699551-A (0.3, 1 or 3 mg/kg s.c.) produced a significant increase in extracellular 5-HT levels. These studies provide evidence for an autoreceptor role for the 5-ht5A receptor in guinea pig brain.

5-ht5A receptors as a therapeutic target.[Pubmed:16516972]

Pharmacol Ther. 2006 Sep;111(3):707-14.

The 5-ht5A 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-ht5A 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-ht5A 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-ht5A 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-ht5A receptor ligands. However, a selective 5-ht5A 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-ht5A receptor, on the basis of these findings, it can be speculated that 5-ht5A receptor-selective ligands might show utility in psychiatric disorders such as schizophrenia and unipolar depression in which cognitive or mood disturbances are a feature.