(−)-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 α7 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 α7 nicotinic receptor is a stron...

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Published in:Journal of medicinal chemistry 2000-11, Vol.43 (22), p.4045-4050
Main Authors: Mullen, George, Napier, James, Balestra, Michael, DeCory, Thomas, Hale, Gregory, Macor, John, Mack, Robert, Loch, James, Wu, Ed, Kover, Alexander, Verhoest, Patrick, Sampognaro, Anthony, Phillips, Eifion, Zhu, Yanyi, Murray, Robert, Griffith, Ronald, Blosser, James, Gurley, David, Machulskis, Anthony, Zongrone, John, Rosen, Alan, Gordon, Jack
Format: Article
Language:English
Subjects:
Biological and medical sciences
Cholinergic system
Medical sciences
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
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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 α7 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 α7 nicotinic receptor, which is highly selective for the rat α7 nicotinic receptor over the α4β2 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 α7 nicotinic receptor affinity.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm000249r