2-(Arylmethyl)-3-substituted quinuclidines as selective alpha 7 nicotinic receptor ligands.
A series of 2-(arylmethyl)-3-substituted quinuclidines was developed as alpha7 neuronal nicotinic acetylcholine receptor (nAChR) agonists based on a putative pharmacophore model. The series is highly selective for the alpha7 over other nAChRs (e.g., the alpha4beta2 of the CNS, and the muscle and ganglionic subtypes) and is functionally tunable at alpha7. One member of the series, (+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide (+)-8l), has potent agonistic activity for the alpha7 nAChR (EC(50)=33nM, I(max)=1.0), at concentrations below those that result in desensitization.
Mazurov
Anatoly
A
Targacept, Inc., Medicinal Chemistry, 200 East First Street, Suite 300, Winston-Salem, NC 27101, USA. anatoly.mazurov@targacept.com <anatoly.mazurov@targacept.com>
Klucik
Jozef
J
Miao
Lan
L
Phillips
Teresa Y
TY
Seamans
Angela
A
Schmitt
Jeffrey D
JD
Hauser
Terry A
TA
Johnson
Raymond T
RT
Miller
Craig
C
D000818:Animals; D002460:Cell Line; D006801:Humans; D008024:Ligands; D011812:Quinuclidines / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D008024:Ligands; D011812:Quinuclidines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor