title: (-)-Spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin-2'-one], a conformationally restricted analogue of acetylcholine, is a highly selective full agonist at the alpha 7 nicotinic acetylcholine receptor.
abstract: Neuronal nicotinic acetylcholine receptors are members of the ligand-gated ion channel receptor superfamily and may play important roles in modulating neurotransmission, cognition, sensory gating, and anxiety. Because of its distribution and abundance in the CNS, the alpha 7 nicotinic receptor is a strong candidate to be involved in some of these functions. In this paper we describe the synthesis and in vitro profile of AR-R17779, (-)-spiro[1-azabicyclo[2.2. 2]octane-3,5'-oxazolidin-2'-one] (4a), a potent full agonist at the rat alpha 7 nicotinic receptor, which is highly selective for the rat alpha 7 nicotinic receptor over the alpha 4 beta 2 subtype. Preliminary SAR of AR-R17779 presented here indicate that there is little scope for modification of this rigid molecule as even minor changes result in significant loss of the alpha 7 nicotinic receptor affinity.
authors.affiliation: Department of Chemistry, AstraZeneca R&D Boston, 3 Biotech, One Innovation Drive, Worcester, Massachusetts 01605, USA. george.mullen@astrazeneca.com
authors.forename: G
authors.initials: G
authors.lastname: Mullen
authors.forename: J
authors.initials: J
authors.lastname: Napier
authors.forename: M
authors.initials: M
authors.lastname: Balestra
authors.forename: T
authors.initials: T
authors.lastname: DeCory
authors.forename: G
authors.initials: G
authors.lastname: Hale
authors.forename: J
authors.initials: J
authors.lastname: Macor
authors.forename: R
authors.initials: R
authors.lastname: Mack
authors.forename: J
authors.initials: J
authors.lastname: Loch
authors.forename: E
authors.initials: E
authors.lastname: Wu
authors.forename: A
authors.initials: A
authors.lastname: Kover
authors.forename: P
authors.initials: P
authors.lastname: Verhoest
authors.forename: A
authors.initials: A
authors.lastname: Sampognaro
authors.forename: E
authors.initials: E
authors.lastname: Phillips
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.forename: R
authors.initials: R
authors.lastname: Murray
authors.forename: R
authors.initials: R
authors.lastname: Griffith
authors.forename: J
authors.initials: J
authors.lastname: Blosser
authors.forename: D
authors.initials: D
authors.lastname: Gurley
authors.forename: A
authors.initials: A
authors.lastname: Machulskis
authors.forename: J
authors.initials: J
authors.lastname: Zongrone
authors.forename: A
authors.initials: A
authors.lastname: Rosen
authors.forename: J
authors.initials: J
authors.lastname: Gordon
mesh_terms: D000109:Acetylcholine / Q000737:chemistry*; D000818:Animals; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D006624:Hippocampus / Q000378:metabolism; D066298:In Vitro Techniques; D018722:Nicotinic Agonists / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D009865:Oocytes / Q000378:metabolism / Q000502:physiology; D016548:Prosencephalon / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014981:Xenopus; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C408128:AR-R 17779; D001952:Bridged-Ring Compounds; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D013141:Spiro Compounds; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2; D000109:Acetylcholine