title: SB-272183, a selective 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptor antagonist in native tissue.
abstract: A novel compound, SB-272183 (5-Chloro-2, 3-dihydro-6-[4-methylpiperazin-1-yl]-1[4-pyridin-4-yl]napth-1-ylaminocarbonyl]-1H-indole), has been shown to have high affinity for human 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors with pK(i) values of 8.0, 8.1 and 8.7 respectively and is at least 30 fold selective over a range of other receptors. [(35)S]-GTPgammaS binding studies showed that SB-272183 acts as a partial agonist at human recombinant 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors with intrinsic activities of 0.4, 0.4 and 0.8 respectively, compared to 5-HT. SB-272183 inhibited 5-HT-induced stimulation of [(35)S]-GTPgammaS binding at human 5-HT(1A) and 5-HT(1B) receptors to give pA(2) values of 8.2 and 8.5 respectively. However, from [(35)S]-GTPgammaS autoradiographic studies in rat and human dorsal raphe nucleus, SB-272183 did not display intrinsic activity up to 10 microM but did block 5-HT-induced stimulation of [(35)S]-GTPgammaS binding. From electrophysiological studies in rat raphe slices in vitro, SB-272183 did not effect cell firing rate up to 1 microM but was able to attenuate (+)8-OH-DPAT-induced inhibition of cell firing to give an apparent pK(b) of 7.1. SB-272183 potentiated electrically-stimulated [(3)H]-5-HT release from rat and guinea-pig cortical slices at 100 and 1000 nM, similar to results previously obtained with the 5-HT(1B) and 5-HT(1D) receptor antagonist, GR127935. Fast cyclic voltammetry studies in rat dorsal raphe nucleus showed that SB-272183 could block sumatriptan-induced inhibition of 5-HT efflux, with an apparent pK(b) of 7.2, but did not effect basal efflux up to 1 microM. These studies show that, in vitro, SB-272183 acts as an antagonist at native tissue 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors.
authors.affiliation: Neuroscience Research and Department of Medicinal Chemistry, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW. Jeannette_M_Watson@sbphrd.com
authors.forename: J
authors.initials: J
authors.lastname: Watson
authors.forename: C
authors.initials: C
authors.lastname: Roberts
authors.forename: C
authors.initials: C
authors.lastname: Scott
authors.forename: I
authors.initials: I
authors.lastname: Kendall
authors.forename: L
authors.initials: L
authors.lastname: Collin
authors.forename: N C
authors.initials: NC
authors.lastname: Day
authors.forename: M H
authors.initials: MH
authors.lastname: Harries
authors.forename: E
authors.initials: E
authors.lastname: Soffin
authors.forename: C H
authors.initials: CH
authors.lastname: Davies
authors.forename: A D
authors.initials: AD
authors.lastname: Randall
authors.forename: T
authors.initials: T
authors.lastname: Heightman
authors.forename: L
authors.initials: L
authors.lastname: Gaster
authors.forename: P
authors.initials: P
authors.lastname: Wyman
authors.forename: C
authors.initials: C
authors.lastname: Parker
authors.forename: G W
authors.initials: GW
authors.lastname: Price
authors.forename: D N
authors.initials: DN
authors.lastname: Middlemiss
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011869:Radioligand Assay; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013462:Sulfur Radioisotopes; D014316:Tritium
chemical_list: C433863:5-chloro-2,3-dihydro-6-(4-methylpiperazin-1-yl)-1-(4-(pyridin-4-yl)naphth-1-ylaminocarbonyl)-1H-indole; C470302:HTR1B protein, human; D007211:Indoles; D010879:Piperazines; D011725:Pyridines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013462:Sulfur Radioisotopes; D014316:Tritium; D012701:Serotonin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin