title: Synthesis and structure-activity relationship studies of 3,6-diazabicyclo[3.2.0]heptanes as novel alpha4beta2 nicotinic acetylcholine receptor selective agonists.
abstract: A series of novel, potent neuronal nicotinic acetylcholine receptor (nAChR) ligands derived from 3,6-diazabicyclo[3.2.0]heptane have been synthesized and evaluated for binding affinity and agonist activity at the alpha4beta2 nAChR subtype. Structure-activity relationship studies of these novel nAChR ligands focused on substitution effects on the pyridine ring, as well as stereo- and regiochemical influences of the 3,6-diazabicyclo[3.2.0]heptane core. Small 5-substituents on the pyridine ring had a modest impact on the binding affinities and functional activities. 6-Bromo, 6-chloro, and 6-methyl substituents on the pyridine ring led to increased binding affinities and improved functional activities. Most of the 6-N-pyridinyl-substituted 3,6-diazabicyclo[3.2.0]heptanes are selective for the alpha4beta2 nAChR subtype. Compounds (1R,5S)-25, (1R,5S)-55, and (1R,5S)-56 were virtually inactive as agonists at the halpha3beta4 nAChR but retained potency and efficacy at the halpha4beta2 nAChR subtype. 3-N-Pyridinyl-substituted series demonstrated more complex SAR. (1R,5R)-39, (1R,5R)-41, and (1R,5R)-42 were found to be much more potent at the halpha3beta4 nAChR subtype, whereas (1R,5R)-38 and (1R,5R)-40 were very selective at the halpha4beta2 nAChR subtype. The SAR studies of these novel ligands led to the discovery of several compounds with interesting in vitro pharmacological profiles.
authors.affiliation: Neuroscience Research, R47W, AP9A-1, Abbott, Abbott Park, Illinois 60064, USA. jianguo.ji@abbott.com
authors.forename: Jianguo
authors.initials: J
authors.lastname: Ji
authors.forename: Michael R
authors.initials: MR
authors.lastname: Schrimpf
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Sippy
authors.forename: William H
authors.initials: WH
authors.lastname: Bunnelle
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.forename: David J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: Connie
authors.initials: C
authors.lastname: Faltynek
authors.forename: Carol S
authors.initials: CS
authors.lastname: Surowy
authors.forename: Tino
authors.initials: T
authors.lastname: Dyhring
authors.forename: Philip K
authors.initials: PK
authors.lastname: Ahring
authors.forename: Michael D
authors.initials: MD
authors.lastname: Meyer
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006536:Heptanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D018722:Nicotinic Agonists / 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; D006536:Heptanes; D008024:Ligands; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D002118:Calcium