Neuronal alpha 7 nicotinic receptors: Candidates for the treatment of Alzheimers and Schizophrenia

[manuelm...@gmail.com]

Neuronal alpha 7 nicotinic receptor (a7nAChR) ligands represent an
emerging class of drug for the treatment of various CNS disorders
associated with cognitive dysfunction. This report describes the proof
of concept supporting the development of this class and analyzes the
various different pharmacological approaches.

The report evaluates the a7nAChR pipeline. Preclinical and clinical
stages candidates are identified and experimental data surrounding
their development described and analyzed. In addition the companies
developing these candidates are profiled.

For more information please click on:
http://www.researchandmarkets.com/product/6f895d/pipeline_report_neuronal_alpha_7_nicotinic

a7nAChRs are selectively expressed in the brain, particularly in
regions implicated in cognitive function and especially Alzheimer's
disease and schizophrenia.

A large body of evidence supports the development of a7nAChR ligands
for the treatment of Alzheimer's disease. Nicotinic agonists support
neuronal survival through a7nAChRs and may therefore counter the
neurodegenerative activity of beta amyloid.

In addition to being involved in neural cell death or survival,
a7nAChRs is also associated with learning and memory. Receptor
agonists enhance LTP, an electrophysiological correlate of memory. In
animal models of Alzheimer's disease a7nAChR agonists have also been
shown to improve memory. Most compelling are recent clinical data
demonstrating improved cognition in patients treated with MEM 3454.

Preclinical and clinical data also exist to suggest that a7nAChR
ligands have a role in the treatment of schizophrenia. In particular,
schizophrenia is associated with defective inhibitory pathways and
hence gating. a7nAChR stimulation enhances inhibitory GABAergic
pathways. Most recently GTS-21 has been shown to improve RBANS score
in a phase 2 study of schizophrenia patients.

Although the a7nAChR is primarily associated with CNS function it is
required for cholinergic inhibition of macrophage TNF release and thus
mediates the anti-inflammatory effect of vagal stimulation.

A number of pharmacological options exist for the development of
a7nAChR ligands. Most promising are partial agonists and allosteric
modulators. Not enough information exists yet to support the
development of antagonists. Allosteric modulators are most promising
for the treatment of schizophrenia.

Partial agonists and allosteric modulators may both be of use in the
treatment of Alzheimer's disease although allosteric modulators may
have less impact as endogenous acetylcholine levels drop with
neurodegeneration.