Evaluation of structurally diverse neuronal nicotinic receptor ligands for selectivity at the alpha6( *) subtype.
Direct comparison of pyridine versus pyrimidine substituents on a small but diverse set of ligands indicates that the pyrimidine substitution has the potential to enhance affinity and/or functional activity at alpha6 subunit-containing neuronal nicotinic receptors (NNRs) and decrease activation of ganglionic nicotinic receptors, depending on the scaffold. The ramifications of this structure-activity relationship are discussed in the context of the design of small molecules targeting smoking cessation.
Breining
Scott R
SR
Department of Medicinal Chemistry, Targacept, Inc., 200 East First St., Suite 300, Winston-Salem, NC 27101, USA.
Bencherif
Merouane
M
Grady
Sharon R
SR
Whiteaker
Paul
P
Marks
Michael J
MJ
Wageman
Charles R
CR
Lester
Henry A
HA
Yohannes
Daniel
D
D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004298:Dopamine / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008024:Ligands; D051379:Mice; D008956:Models, Chemical; D009538:Nicotine / Q000737:chemistry; D010300:Parkinson Disease / Q000188:drug therapy; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry; D011978:Receptors, Nicotinic / Q000737:chemistry*; D016540:Smoking Cessation / Q000379:methods*; D013329:Structure-Activity Relationship
C470410:CHRNA6 protein, human; D008024:Ligands; D011743:Pyrimidines; D011978:Receptors, Nicotinic; D009538:Nicotine; D004298:Dopamine