Discovery of 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744) as a novel positive allosteric modulator of the alpha7 nicotinic acetylcholine receptor.
The discovery of a series of pyrrole-sulfonamides as positive allosteric modulators (PAM) of alpha7 nAChRs is described. Optimization of this series led to the identification of 19 (A-867744), a novel type II PAM with good potency and selectivity. Compound 19 showed acceptable pharmacokinetic profile across species and brain levels sufficient to modulate alpha7 nAChRs. In a rodent model of sensory gating, 19 normalized gating deficits. These results suggest that 19 represents a novel class of molecules capable of allosteric modulation of the alpha7 nAChRs.
Faghih
Ramin
R
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA. ramin.faghih@abbott.com
Gopalakrishnan
Sujatha M
SM
Gronlien
Jens Halvard
JH
Malysz
John
J
Briggs
Clark A
CA
Wetterstrand
Caroline
C
Ween
Hilde
H
Curtis
Michael P
MP
Sarris
Kathy A
KA
Gfesser
Gregory A
GA
El-Kouhen
Rachid
R
Robb
Holly M
HM
Radek
Richard J
RJ
Marsh
Kennan C
KC
Bunnelle
William H
WH
Gopalakrishnan
Murali
M
D000494:Allosteric Regulation; D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D055808:Drug Discovery; D051379:Mice; D008861:Microsomes; D009865:Oocytes; D018408:Patch-Clamp Techniques; D010599:Pharmacokinetics; D011758:Pyrroles / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D055139:Sensory Gating / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000096926:Benzenesulfonamides
D011758:Pyrroles; D011978:Receptors, Nicotinic; D013449:Sulfonamides; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000096926:Benzenesulfonamides; C542089:4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide; C579166:Chrna7 protein, mouse