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Targeting the nicotinic alpha7 acetylcholine receptor to enhance cognition in disease.

Wallace TL, Porter RH

Center for Neuroscience, SRI International, 333 Ravenswood Avenue, M/S 100-69, Menlo Park, CA 94025, USA. tanya.wallace@sri.com

A promising drug target currently under investigation to improve cognitive deficits in neuropsychiatric and neurological disorders is the neuronal nicotinic alpha7 acetylcholine receptor (α7nAChR). Improving cognitive impairments in diseases such as Alzheimer's (AD) and schizophrenia remains a large unmet medical need, and the α7nAChR has many properties that make it an attractive therapeutic target. The α7nAChR is a ligand gated ion channel that has particularly high permeability to Ca(2+) and is expressed in key brain regions involved in cognitive processes (e.g., hippocampus). The α7nAChRs are localized both pre-synaptically, where they can regulate neurotransmitter release, and post-synaptically where they can activate intracellular signaling cascades and influence downstream processes involved in learning and memory. In particular, activation of the α7nAChR with small molecule agonists enhances long-term potentiation, an in vitro model of synaptic plasticity, and improves performance across multiple cognitive domains in rodents, monkeys, and humans. Positive allosteric modulation of the α7nAChR offers an alternate approach to direct agonism that could prove to be particularly beneficial in certain disease populations where smoking nicotine is prevalent (e.g., schizophrenia) and could interfere with an orthosteric agonist approach. The current review focuses on the neurobiology of the α7nAChR, its role in cognition and the development status of some of the most promising molecules advancing for the treatment of cognitive dysfunction in disease.

Published 25 August 2011 in Biochem Pharmacol, 82(8): 891-903.
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Articles on Pharmacology published 25 August 2011:

Progress and challenges in the study of α6-containing nicotinic acetylcholine receptors.   Biochem Pharmacol, 82(8): 862-72.

Recent progress has been made in the understanding of the anatomical distribution, composition, and physiological role of nicotinic acetylcholine receptors containing the α6 subunit. Extensive study by many researchers has indicated that a collection of α6-containing receptors representing a nicotinic sub-family is relevant in preclinical models of nicotine self-administration and locomotor activity. Due to a number of technical difficulties, the state of the art of in vitro model systems ... [Abstract] [Full-text]

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Articles on Pharmacology published 9 August 2011:

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The Medicines and Healthcare products Regulatory Authority (MHRA) is the government body with responsibility for regulating new and existing medicines and medical devices in the United Kingdom. The Yellow Card scheme is a well-established pharmacovigilance system that collects voluntary reports of adverse effects associated with therapeutic drug use. In contrast, data concerning clinical toxicological effects are more poorly characterised. No comparable surveillance processes exist in the ... [Abstract] [Full-text]

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