title: 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-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.
authors.affiliation: Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park (North), Harlow, Essex, UK. david.r.thomas@gsk.com
authors.forename: David R
authors.initials: DR
authors.lastname: Thomas
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Soffin
authors.forename: Claire
authors.initials: C
authors.lastname: Roberts
authors.forename: James N C
authors.initials: JN
authors.lastname: Kew
authors.forename: Raul M
authors.initials: RM
authors.lastname: de la Flor
authors.forename: Lee A
authors.initials: LA
authors.lastname: Dawson
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Fry
authors.forename: Sara A
authors.initials: SA
authors.lastname: Coggon
authors.forename: Stefania
authors.initials: S
authors.lastname: Faedo
authors.forename: Philip D
authors.initials: PD
authors.lastname: Hayes
authors.forename: David F
authors.initials: DF
authors.lastname: Corbett
authors.forename: Ceri H
authors.initials: CH
authors.lastname: Davies
authors.forename: Jim J
authors.initials: JJ
authors.lastname: Hagan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000166:cytology / Q000187:drug effects; D002460:Cell Line; D015283:Citalopram / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004563:Electrochemistry / Q000379:methods; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006168:Guinea Pigs; D006801:Humans; D007554:Isotopes / Q000493:pharmacokinetics; D008238:Lysergic Acid Diethylamide / Q000493:pharmacokinetics; D008297:Male; D017551:Microdialysis / Q000379:methods; D009474:Neurons / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011869:Radioligand Assay / Q000379:methods; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics
chemical_list: D001713:Biphenyl Compounds; D015283:Citalopram; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D007554:Isotopes; D008238:Lysergic Acid Diethylamide; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D012701:Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C515421:SB-699551-A; C078730:serotonin 5 receptor; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide