title: Synthesis, nicotinic acetylcholine receptor binding affinities, and molecular modeling of constrained epibatidine analogues.
abstract: Conformationally constrained epibatidine analogues 20a,b and 23a,b were synthesized using a radical cyclization as the key step. Radioligand displacement assays to six defined rat nicotinic acetylcholine receptor (nAChR) subtypes showed that 20a,b bind with moderate affinities, while 23a,b have low affinities. 20a exhibits higher affinity for the beta2 containing subtype than for the beta4 containing counterpart, while 20b possesses reversed selectivity. Modeling studies suggest that the spatial distribution of the ligand's atoms around the pharmacophore elements may control their nAChR subtype selectivity.
authors.affiliation: Drug Discovery Program, Department of Neurology, Georgetown University Medical Center, 3900 Reservoir Road, NW, Washington, DC 20057, USA.
authors.forename: Zhi-Liang
authors.initials: ZL
authors.lastname: Wei
authors.forename: Pavel A
authors.initials: PA
authors.lastname: Petukhov
authors.forename: Yingxian
authors.initials: Y
authors.lastname: Xiao
authors.forename: Werner
authors.initials: W
authors.lastname: Tückmantel
authors.forename: Clifford
authors.initials: C
authors.lastname: George
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Kellar
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D003500:Cyclization; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D021122:Protein Subunits; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D021122:Protein Subunits; D011725:Pyridines; D011978:Receptors, Nicotinic; C082748:epibatidine