Novel α3β4 nicotinic acetylcholine receptor-selective ligands. Discovery, structure-activity studies, and pharmacological evaluation.
Antagonist activity at the α3β4 nicotinic acetylcholine receptor (nAChR) is thought to contribute to the antiaddictive properties of several compounds. However, truly selective ligands for the α3β4 nAChR have not been available. We report the discovery and SAR of a novel class of compounds that bind to the α3β4 nAChR and have no measurable affinity for the α4β2 or α7 subtype. In functional assays the lead compound antagonized epibatidine-induced Ca(2+) flux in α3β4-transfected cells in a noncompetitive manner.
Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo Park, California 94025, USA. nurulain@astraeatherapeutics.com
Nurulain
N
Zaveri
Faming
F
Jiang
Cris
C
Olsen
Willma
W
Polgar
Lawrence
L
Toll
D053961:Azabicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014162:Transfection; D064569:alpha7 Nicotinic Acetylcholine Receptor
C554514:1-(9-methyl-9-azabicyclo(3.3.1)non-3-yl)-1,3-dihydro-2H-indol-2-one; D053961:Azabicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; C579167:Chrna7 protein, human; D007211:Indoles; D008024:Ligands; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403530:nicotinic receptor alpha3beta4; C403531:nicotinic receptor alpha4beta2; C082748:epibatidine