8-Piperazinyl-2,3-dihydropyrrolo[3,2-g]isoquinolines: potent, selective, orally bioavailable 5-HT1 receptor ligands.
Heightman TD,
Gaster LM,
Pardoe SL,
Pilleux JP,
Hadley MS,
Middlemiss DN,
Price GW,
Roberts C,
Scott CM,
Watson JM,
Gordon LJ,
Holland VA,
Powles J,
Riley GJ,
Stean TO,
Trail BK,
Upton N,
Austin NE,
Ayrton AD,
Coleman T,
Cutler 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.
PMID: 16039851 [PubMed - indexed for MEDLINE]