title: Structure-activity studies of diazabicyclo[3.3.0]octane-substituted pyrazines and pyridines as potent α4β2 nicotinic acetylcholine receptor ligands.
abstract: A series of diazabicyclo[3.3.0]octane substituted pyridines and pyrazines was synthesized and characterized at the α4β2 neuronal nicotinic acetylcholine receptor (nAChR). The compounds were designed to mimic the profile of ABT-089, high affinity binding ligand for the α4β2 nAChR, with limited agonist activity. Carboxamide derivatives of 3-(diazabicyclo[3.3.0]octane)-substituted pyridines or 2-(diazabicyclo[3.3.0]octane)-substituted pyrazines were found to have the desired binding and activity profile. The structure-activity relationship of these compounds is presented.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA. marc.scanio@abbott.com
authors.forename: Marc J C
authors.initials: MJ
authors.lastname: Scanio
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: William H
authors.initials: WH
authors.lastname: Bunnelle
authors.forename: David J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: Rosalind J
authors.initials: RJ
authors.lastname: Helfrich
authors.forename: John
authors.initials: J
authors.lastname: Malysz
authors.forename: Kirsten K
authors.initials: KK
authors.lastname: Thorin-Hagene
authors.forename: Ceclia E
authors.initials: CE
authors.lastname: Van Handel
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Lee
authors.forename: Murali
authors.initials: M
authors.lastname: Gopalakrishnan
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D054333:Drug Partial Agonism; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D009474:Neurons / Q000378:metabolism; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011759:Pyrrolidines / Q000737:chemistry; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D018722:Nicotinic Agonists; D011719:Pyrazines; D011725:Pyridines; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; C403531:nicotinic receptor alpha4beta2; C108326:pozanicline