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SB-699,551; A novel anxiolytic and possible anti-depressant?

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This one is demonstrated as a selective serotonin 5-HT5A antagonist; presumably, this would raise cyclic AMP levels and increase serotonin due to the 5A receptor being yet another serotonin autoreceptor - however, paradoxically there may be a net decrease in cAMP levels due to the interexchangeable / compensatory increase in 5-HT1A receptors/activity.

The benefit here would lie in coordination with other compounds - a 5A antagonist itself may possess anti-depressant properties though by acting through downstream regulation of serotonin activity....

Seeing as how 5A knockout mice did not display anxiety - it shows a role for this compound or other 5A antagonists to reduce anxiety.

This would also be consistent with the 5A's role in regulating pituitary activity and it's concentration in hypothalamic regions.

http://www.ncbi.nlm.nih.gov/pubmed/16002289
http://www.ncbi.nlm.nih.gov/pubmed/16516972
http://en.wikipedia.org/wiki/SB-699,551

Neuropharmacology. 2006 Sep;51(3):566-77. Epub 2006 Jul 17.
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.
Thomas DR1, Soffin EM, Roberts C, Kew JN, de la Flor RM, Dawson LA, Fry VA, Coggon SA, Faedo S, Hayes PD, Corbett DF, Davies CH, Hagan JJ.
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Abstract
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.
PMID: 16846620 [PubMed - indexed for MEDLINE]

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