8-Piperazinyl-2,3-dihydropyrrolo[3,2-g]isoquinolines: potent, selective, orally bioavailable 5-HT1 receptor ligands.
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.
Heightman
Tom D
TD
High Throughput Chemistry, Discovery Research, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow Essex CM19 5AW, UK. Tom.D.Heightman@gsk.com
Gaster
Laramie M
LM
Pardoe
Sarah L
SL
Pilleux
Jean-Pierre
JP
Hadley
Michael S
MS
Middlemiss
Derek N
DN
Price
Gary W
GW
Roberts
Claire
C
Scott
Claire M
CM
Watson
Jeannette M
JM
Gordon
Laurie J
LJ
Holland
Vicky A
VA
Powles
Jenifer
J
Riley
Graham J
GJ
Stean
Tania O
TO
Trail
Brenda K
BK
Upton
Neil
N
Austin
Nigel E
NE
Ayrton
Andrew D
AD
Coleman
Tanya
T
Cutler
Leanne
L
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
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