Synthesis and structure-activity relationships of 5-substituted pyridine analogues of 3.
In an effort to probe the steric influence of C5 substitution of the pyridine ring on CNS binding affinity, analogues of 1 substituted with a bulky moiety--such as phenyl, substituted phenyl, or heteroaryl-were synthesized and tested in vitro for neuronal nicotinic acetylcholine receptor binding affinity. The substituted analogues exhibited Ki values ranging from 0.055 to 0.69 nM compared to a Ki value of 0.15 nM for compound 1. Assessment of functional activity at subtypes of neuronal nicotinic acetylcholine receptors led to identify several agonists and antagonists.
Neurological and Urological Diseases Research, D-47W, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064-3500, USA. nanhorng.lin@abbott.com
N H
NH
Lin
Y
Y
Li
Y
Y
He
M W
MW
Holladay
T
T
Kuntzweiler
D J
DJ
Anderson
J E
JE
Campbell
S P
SP
Arneric
D002460:Cell Line; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D018722:Nicotinic Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
C116733:3-(2-(pyrrolidinyl)methoxy)pyridine; D008024:Ligands; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D011759:Pyrrolidines; D011978:Receptors, Nicotinic