title: Diazaspirocyclic compounds as selective ligands for the α4β2 nicotinic acetylcholine receptor.
abstract: Diazaspirocyclic ligands have been synthesized in four steps as selective α4β2 nicotinic acetylcholine receptor antagonists. Structural assignment of 1-(pyridin-3-yl)-2-spiropyrrolidino-3,2'-1-azabiclo[2.2.1]heptane 2, was confirmed using a combination of NMR experiments on a key intermediate, spirolactam 9. All three target compounds synthesized in this diazaspirocyclic series exhibited high affinity (K(i)<35 nM) at the human α4β2 nAChR subtype, and very low affinity for the human α7, α3β4 (ganglion) and α1β1γδ (muscle) subtypes (K(i)>500 nM).
authors: Targacept, Inc., 200 East 1st Street, Winston-Salem, NC 27101-4165, United States. jpstrach@yahoo.com
authors: Jon-Paul
authors: JP
authors: Strachan
authors: Jarrett J
authors: JJ
authors: Farias
authors: Jenny
authors: J
authors: Zhang
authors: William S
authors: WS
authors: Caldwell
authors: Balwinder S
authors: BS
authors: Bhatti
mesh_terms: D001372:Aza Compounds / Q000737:chemistry*; D006536:Heptanes / Q000737:chemistry; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D018733:Nicotinic Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001372:Aza Compounds; D006536:Heptanes; D008024:Ligands; D018733:Nicotinic Antagonists; D020033:Protein Isoforms; D011978:Receptors, Nicotinic; D013141:Spiro Compounds; C403531:nicotinic receptor alpha4beta2