title: 8-Piperazinyl-2,3-dihydropyrrolo[3,2-g]isoquinolines: potent, selective, orally bioavailable 5-HT1 receptor ligands.
abstract: The novel 8-piperazinyl-2,3-dihydropyrroloisoquinoline template was synthesized in nine steps. The template was N-substituted to give a series of compounds showing binding to human cloned 5-HT1A, 5-HT1B and 5-HT1D receptors with pKi's greater than 9 and selectivities up to 1000-fold against other serotonin, dopamine and adrenergic receptors. Several compounds were shown to possess weak partial agonist activity in cloned receptors, which translated to antagonism in in vitro studies.
authors.affiliation: High Throughput Chemistry, Discovery Research, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow Essex CM19 5AW, UK. Tom.D.Heightman@gsk.com
authors.forename: Tom D
authors.initials: TD
authors.lastname: Heightman
authors.forename: Laramie M
authors.initials: LM
authors.lastname: Gaster
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Pardoe
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pilleux
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hadley
authors.forename: Derek N
authors.initials: DN
authors.lastname: Middlemiss
authors.forename: Gary W
authors.initials: GW
authors.lastname: Price
authors.forename: Claire
authors.initials: C
authors.lastname: Roberts
authors.forename: Claire M
authors.initials: CM
authors.lastname: Scott
authors.forename: Jeannette M
authors.initials: JM
authors.lastname: Watson
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Gordon
authors.forename: Vicky A
authors.initials: VA
authors.lastname: Holland
authors.forename: Jenifer
authors.initials: J
authors.lastname: Powles
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Riley
authors.forename: Tania O
authors.initials: TO
authors.lastname: Stean
authors.forename: Brenda K
authors.initials: BK
authors.lastname: Trail
authors.forename: Neil
authors.initials: N
authors.lastname: Upton
authors.forename: Nigel E
authors.initials: NE
authors.lastname: Austin
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Ayrton
authors.forename: Tanya
authors.initials: T
authors.lastname: Coleman
authors.forename: Leanne
authors.initials: L
authors.lastname: Cutler
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001923:Brain Chemistry; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008024:Ligands; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D007546:Isoquinolines; D008024:Ligands; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A