title: Design, synthesis and discovery of picomolar selective α4β2 nicotinic acetylcholine receptor ligands.
abstract: Developing novel and selective compounds that desensitize α4β2 nicotinic acetylcholine receptors (nAChRs) could provide new effective treatments for nicotine addiction, as well as other disorders. Here we report a new class of nAChR ligands that display high selectivity and picomolar binding affinity for α4β2 nicotinic receptors. The novel compounds have Ki values in the range of 0.031-0.26 nM and properties that should make them good candidates as drugs acting in the CNS. The selected lead compound 1 (VMY-2-95) binds with high affinity and potently desensitizes α4β2 nAChRs. At a dose of 3 mg/kg, compound 1 significantly reduced rat nicotine self-administration. The overall results support further characterizations of compound 1 and its analogues in preclinical models of nicotine addiction and perhaps other disorders involving nAChRs.
authors.affiliation: Center for Drug Discovery, Georgetown University Medical Center , 3970 Reservoir Road NW, Research Building, EP-07, Washington, D.C. 20057, United States.
authors.forename: Venkata M
authors.initials: VM
authors.lastname: Yenugonda
authors.forename: Yingxian
authors.initials: Y
authors.lastname: Xiao
authors.forename: Edward D
authors.initials: ED
authors.lastname: Levin
authors.forename: Amir H
authors.initials: AH
authors.lastname: Rezvani
authors.forename: Thao
authors.initials: T
authors.lastname: Tran
authors.forename: Nour
authors.initials: N
authors.lastname: Al-Muhtasib
authors.forename: Niaz
authors.initials: N
authors.lastname: Sahibzada
authors.forename: Teresa
authors.initials: T
authors.lastname: Xie
authors.forename: Corinne
authors.initials: C
authors.lastname: Wells
authors.forename: Susan
authors.initials: S
authors.lastname: Slade
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Johnson
authors.forename: Sivanesan
authors.initials: S
authors.lastname: Dakshanamurthy
authors.forename: Hye-Sik
authors.initials: HS
authors.lastname: Kong
authors.forename: York
authors.initials: Y
authors.lastname: Tomita
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Mikell
authors.initials: M
authors.lastname: Paige
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Kellar
authors.forename: Milton L
authors.initials: ML
authors.lastname: Brown
mesh_terms: D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012984:Software; D013329:Structure-Activity Relationship
chemical_list: C587000:3-(azetidin-2-ylmethoxy)-5-(phenylethynyl)pyridine; D001384:Azetidines; D008024:Ligands; D011725:Pyridines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2