Discovery and structure-activity relationship of quinuclidine benzamides as agonists of alpha7 nicotinic acetylcholine receptors.
A library of benzamides was tested for alpha7 nicotinic acetylcholine receptor (nAChR) agonist activity using a chimeric receptor in a functional, cell-based, high-throughput assay. From this library, quinuclidine benzamides were found to have alpha7 nAChR agonist activity. The SAR diverged from the activity of this compound class verses the 5-HT(3) receptor, a structural homologue of the alpha7 nAChR. PNU-282987, the most potent compound from this series, was also shown to open native alpha7 nAChRs in cultured rat neurons and to reverse an amphetamine-induced gating deficit in rats.
Bodnar
Alice L
AL
Department of Neuroscience, Global Research and Development, Pfizer Inc., Groton, CT, USA.
Cortes-Burgos
Luz A
LA
Cook
Karen K
KK
Dinh
Dac M
DM
Groppi
Vincent E
VE
Hajos
Mihaly
M
Higdon
Nicole R
NR
Hoffmann
William E
WE
Hurst
Raymond S
RS
Myers
Jason K
JK
Rogers
Bruce N
BN
Wall
Theron M
TM
Wolfe
Mark L
ML
Wong
Erik
E
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D020650:Combinatorial Chemistry Techniques; D006624:Hippocampus / Q000166:cytology; D015640:Ion Channel Gating / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011812:Quinuclidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D058827:Serotonin 5-HT3 Receptor Agonists; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor
D001549:Benzamides; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D011812:Quinuclidines; D011978:Receptors, Nicotinic; D058827:Serotonin 5-HT3 Receptor Agonists; D064569:alpha7 Nicotinic Acetylcholine Receptor