(-)-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...

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Published in:Journal of medicinal chemistry 2000-11, Vol.43 (22), p.4045-4050
Main Authors: Mullen, G, Napier, J, Balestra, M, DeCory, T, Hale, G, Macor, J, Mack, R, Loch, 3rd, J, Wu, E, Kover, A, Verhoest, P, Sampognaro, A, Phillips, E, Zhu, Y, Murray, R, Griffith, R, Blosser, J, Gurley, D, Machulskis, A, Zongrone, J, Rosen, A, Gordon, J
Format: Article
Language:English
Subjects:
Acetylcholine - chemistry
alpha7 Nicotinic Acetylcholine Receptor
Animals
Bridged-Ring Compounds - chemical synthesis
Bridged-Ring Compounds - metabolism
Bridged-Ring Compounds - pharmacology
Hippocampus - metabolism
In Vitro Techniques
Nicotinic Agonists - chemical synthesis
Nicotinic Agonists - metabolism
Nicotinic Agonists - pharmacology
Oocytes - metabolism
Oocytes - physiology
Prosencephalon - metabolism
Radioligand Assay
Rats
Receptors, Nicotinic - drug effects
Receptors, Nicotinic - metabolism
Spiro Compounds - chemical synthesis
Spiro Compounds - metabolism
Spiro Compounds - pharmacology
Stereoisomerism
Structure-Activity Relationship
Xenopus
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Summary: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.
ISSN:0022-2623
DOI:10.1021/jm000249r