(-)-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

  • J Med Chem. 2000 Nov 2;43(22):4045-50. doi: 10.1021/jm000249r.
G Mullen  1 ,  J Napier ,  M Balestra ,  T DeCory ,  G Hale ,  J Macor ,  R Mack ,  J Loch 3rd ,  E Wu ,  A Kover ,  P Verhoest ,  A Sampognaro ,  E Phillips ,  Y Zhu ,  R Murray ,  R Griffith ,  J Blosser ,  D Gurley ,  A Machulskis ,  J Zongrone ,  A Rosen ,  J Gordon
Affiliations
  • 1. Department of Chemistry, AstraZeneca R&D Boston, 3 Biotech, One Innovation Drive, Worcester, Massachusetts 01605, USA. [email protected]
PMID: 11063601 DOI: 10.1021/jm000249r
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.

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