8-Piperazinyl-2,3-dihydropyrrolo[3,2-g]isoquinolines: potent, selective, orally bioavailable 5-HT1 receptor ligands.
Bioorganic & medicinal chemistry letters 2005 Oct 1; 15(19):4370-4
Heightman T TD, Gaster L LM, Pardoe S SL, Pilleux J JP, Hadley M MS, Middlemiss D DN, Price G GW, Roberts C C, Scott C CM, Watson J JM, Gordon L LJ, Holland V VA, Powles J J, Riley G GJ, Stean T TO, Trail B BK, Upton N N, Austin N NE, Ayrton A AD, Coleman T T, Cutler L L
High Throughput Chemistry, Discovery Research, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow Essex CM19 5AW, UK. Tom.D.Heightman@gsk.com
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.