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RJR-2403: A CNS-Selective Nicotinic Agonist with Therapeutic Potential

  • Patrick M. Lippiello
  • Merouane Bencherif
  • William S. Caldwell
  • Sherry R. Arrington
  • Kathy W. Fowler
  • M. Elisa Lovette
  • Leigh K. Reeves
Part of the Advances in Alzheimer Disease Therapy book series (AADT)

Abstract

In recent years molecular cloning studies have resulted in the discovery of multiple genes encoding a variety of structural and functional subunits for nicotinic cholinergic receptors (nAChR) (Galzi and Changeux, 1995), 11 having neuronal localization (α2–α9, β2–β4) and 5 expressed in skeletal muscle (α1, β1,γ, δ, ε). This molecular diversity opens up the possibility of complex receptor subtype expression both in the autonomic (PNS) and central (CNS) nervous systems, possibly explaining the complex pharmacological effects of nicotine and other classic nicotinic cholinergic agonists that do not discriminate among the various receptor subtypes expressed in the CNS and PNS. The importance of understanding this complexity is emphasized by the growing body of evidence suggesting that compromised CNS nicotinic cholinergic neurotransmission may play a key role in a variety of CNS and PNS pathologies. In this regard, there is growing interest in the use of nicotinic agonists for the treatment of Alzheimer’s disease (AD) (Williams et al., 1994). One consistent feature of this disease is a decline in the function of cholinergic systems. The loss of neurons that release acetylcholine, a key neurotransmitter in learning and memory mechanisms, initially motivated an intense but disappointing search for replacement therapies targeting muscarinic receptors. On the other hand, epidemiological studies have reported an inverse correlation between the incidence of AD and smoking (van Duijn and Hofman, 1991), supporting the notion that nicotinic pharmacology underlies an apparent protective effect.

Keywords

Reference Memory Ibotenic Acid Nicotinic Agonist nAChR Subtype Neuronal Nicotinic Acetylcholine Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Birkhäuser Boston 1997

Authors and Affiliations

  • Patrick M. Lippiello
    • 1
  • Merouane Bencherif
    • 1
  • William S. Caldwell
    • 1
  • Sherry R. Arrington
    • 1
  • Kathy W. Fowler
    • 1
  • M. Elisa Lovette
    • 1
  • Leigh K. Reeves
    • 1
  1. 1.Research and DevelopmentR.J. ReynoldsWinston-SalemUSA

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