Nicotinic Receptors as a Nootropic Target

nicotinic acetylcholine receptors

The alpha-7 nicotinic receptor, a type of nicotinic receptor comprised entirely of alpha7 subunits, is implicated in long term and working memory.

A number of alpha7 nicotinic acetylcholine receptor agonists are under clinical development for the treatment of schizophrenia and alzheimer’s disease.

Nicotine and Schizophrenia

Alpha7 nicotinic receptor stimulation likely underlies the cognitive enhancing effects of nicotine. The alpha-7 nicotinic receptor has been identified as a therapeutic target in the treatment of schizophrenia due to the cognitive deficits that coincide with the onset of the disease, typically in adolescence. It is hypothesized that the dramatically increased prevalence of smoking amongst subjects with schizophrenia may be a form of self-medication to offset shizophrenia-related cognitive impairments and some of the cognitive side effects of antipsychotic medications.

Nicotinic Receptors and Alzheimer’s Disease

In Alzheimer’s disease, the density of nicotinic receptors relative to muscarinic receptors is reduced. Alpha7 nicotinic receptor are presnet in brain regions that play well-characterized roles in cognition, including the cerebral cortex and hippocampus.

The theoretical rational for targeting alpha7 nicotinic receptors is as follows:

  • The alpha7 receptor is highly calcium-permeable; calcium is an important second-messenger that stimulates neurotransmission, protein kinase activation, calcineurins, and nitric oxide synthetases.
  • The alpha7 receptor uniquely mediates the neuroprotective effects of nicotinic agonists against beta-amyloid, and nerve growth factor (NGF) depletion.
  • Stimulation of this receptor enhances cognition in animal models and healthy human subjects alike.
  • Chronic administration of some nicotinic agonists (e.g., DMXBA) does not lead to significant receptor upregulation or downregulation.

Alpha7 Nicotinic Agonists In The Drug Development Pipeline

Compound Pharmaceutical Company Location Indication Phase Website
EVP-6124 EnVivo Pharmaceuticals Watertown, MA Alzheimer's Disease Phase II www.envivopharma.com
TC-5619 Targacept Winston-Salem, NC Alzheimer's Disease Phase I www.targacept.com
ABT-126 AbbVie North Chicago, IL Alzheimer's Disease Phase II www.abbvie.com
Bradanicline (TC-5619) AstraZeneca London, UK Schizophrenia Phase II (abandoned) www.astrazenica.com
GTS (DMBX-A)
PHA-543,613
WAY-317,538

 

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