(-)-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.
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.
Mullen
G
G
Department of Chemistry, AstraZeneca R&D Boston, 3 Biotech, One Innovation Drive, Worcester, Massachusetts 01605, USA. george.mullen@astrazeneca.com
Napier
J
J
Balestra
M
M
DeCory
T
T
Hale
G
G
Macor
J
J
Mack
R
R
Loch
J
J
Wu
E
E
Kover
A
A
Verhoest
P
P
Sampognaro
A
A
Phillips
E
E
Zhu
Y
Y
Murray
R
R
Griffith
R
R
Blosser
J
J
Gurley
D
D
Machulskis
A
A
Zongrone
J
J
Rosen
A
A
Gordon
J
J
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
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