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

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-ht 5A receptor function in guinea pig brain. SB-699551-A competitively antagonised 5-HT-stimulated [ 35 S]GTPγS binding to membranes from human embryonic kidney (HEK293) cells transiently expressing the guinea pig 5-ht 5A receptor (p A 2 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-HT 2A/C and 5-HT 7 ) reported to modulate central 5-HT neurotransmission in the guinea pig. In guinea pig dorsal raphe slices, SB-699551-A (1 μM) 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-HT 1A 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-ht 5A receptor in guinea pig brain.