title: Coaxing a pyridine nucleus to give up its aromaticity: synthesis and pharmacological characterization of novel conformationally restricted analogues of nicotine and anabasine.
abstract: A series of novel nicotine and anabasine related conformationally restricted compounds including those with pi-bonds in the connecting tether were synthesized following the hitherto unprecedented phenylsulfanyl group assisted generation of pyridine o-quinodimethane intermediates and their trapping by an intramolecular Diels-Alder reaction. Pharmacological characterization of some of these analogues at activating alpha3beta4 nAChRs was investigated, and constrained anabasine analogues 35 and 43 as well as constrained nicotine analogue 42 were found to exhibit moderately potent nicotinic agonist activity. Of special note is the fact that the pyrrolidinic nitrogen in these compounds is bound to a carbomethoxy group and, therefore, is not free to be protonated unlike all the known analogues of nicotine and anabasine, specifically designed as nAChRs agonists/antagonists. The structure-activity relationship studies indicate that when pi-cation interaction is absent, the position of chlorine atom in the pyridine ring and steric bulk at the connecting tether between the pyridine and pyrrolidine ring of the constrained nicotinic ligands are important descriptors for their binding affinity at alpha4beta2 and alpha3beta4 nAChRs as well as the subtype selectivity issue. These findings are likely to improve our understanding of the structural requirements for selectivity, which, at present, is probably the most important goal in the field of nicotinic ligands.
authors.affiliation: Department of Chemistry, Indian Institute of Technology, Kharagpur-721302, India. tksr@chem.iitkgp.ernet.in
authors.forename: Tarun K
authors.initials: TK
authors.lastname: Sarkar
authors.forename: Sankar
authors.initials: S
authors.lastname: Basak
authors.forename: Irving
authors.initials: I
authors.lastname: Wainer
authors.forename: Ruin
authors.initials: R
authors.lastname: Moaddel
authors.forename: Rika
authors.initials: R
authors.lastname: Yamaguchi
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Jozwiak
authors.forename: Hui-Ting
authors.initials: HT
authors.lastname: Chen
authors.forename: Chun-Cheng
authors.initials: CC
authors.lastname: Lin
mesh_terms: D000691:Anabasine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D018360:Crystallography, X-Ray; D008968:Molecular Conformation; D009538:Nicotine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; D009538:Nicotine; D000691:Anabasine