title: Synthesis of bridgehead-substituted azabicyclo[2.2.1]heptane and -[3.3.1]nonane derivatives for the elaboration of α7 nicotinic ligands.
abstract: Azabicyclo[2.2.1]heptane and -[3.3.1]nonane scaffolds (X = Cl, Br) containing a pyridinyl substituent at the bridgehead position were prepared via two complementary chemical pathways, either by the transformation of a methoxy group into a synthetically valuable chlorine atom at the C-6 position of the pyridine moiety or by means of a regioselective C-6 deprotonation/halogenation process of the pyridine moiety exemplified by chlorination or bromination. These newly generated scaffolds were then engaged in Suzuki-Miyaura coupling reactions to provide α7 nicotinic ligands. Both chemical series were evaluated in vitro for their affinity at α7 nicotinic receptors, revealing nanomolar potency with significant selectivity over the α4β2 nicotinic subtype. These approaches offer a general access to these α7 nicotinic scaffolds and ligands.
authors.affiliation: Exploratory Unit, Sanofi Aventis R & D, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin Cedex, France. franck.slowinski@sanofi-aventis.com
authors.forename: Franck
authors.initials: F
authors.lastname: Slowinski
authors.forename: Omar
authors.initials: O
authors.lastname: Ben Ayad
authors.forename: Julien
authors.initials: J
authors.lastname: Vache
authors.forename: Mourad
authors.initials: M
authors.lastname: Saady
authors.forename: Odile
authors.initials: O
authors.lastname: Leclerc
authors.forename: Alistair
authors.initials: A
authors.lastname: Lochead
mesh_terms: D000473:Alkanes / Q000737:chemistry*; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D053961:Azabicyclo Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002712:Chlorides / Q000737:chemistry; D054879:Halogenation; D006536:Heptanes / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011522:Protons; D011725:Pyridines / Q000737:chemistry; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism; D013237:Stereoisomerism; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D000473:Alkanes; D053961:Azabicyclo Compounds; D002712:Chlorides; C579167:Chrna7 protein, human; D006536:Heptanes; D008024:Ligands; D018722:Nicotinic Agonists; D011522:Protons; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2; C017573:nonane