Nicotine has long been known to improve cognitive function, but its adverse effects make it problematic as a treatment for diseases of cognitive dysfunction. Recent research has revealed that certain subtypes of nicotinic acetylcholinesterase receptors (nAChRs) in the brain are involved in cognitive function. Agents that target these nAChRs have shown promise in Alzheimer' s disease, attention-defi cit/hyperactivity disorder, schizophrenia, and mild cognitive impairment. Research also suggests that these agents may not only improve cognition but also be neuroprotective. Thus, hopes have been raised that these agents may be disease-modifying therapeutics for neurodegenerative diseases.

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Although the role of neural nicotinic receptors in cognition has been known since the 1980s, development of nAChR subtype-specific agonists has proven difficult. Why have previous agents failed during early stages of development?
Several small biopharmaceutical companies have subtype-specific nAChRs in clinical development for diseases of cognitive dysfunction. The most advanced of these agents are in Phase II. Which of these companies have agents in Phase II trials, and which Big Pharma companies have partnered with them? When might nAChR agents now in development reach the market?
Several pharmaceutical companies are expected to enter candidate nAChR agonists for the treatment of cognitive disorders into the clinic from their in-house programs. Which Big Pharma company has already entered its smoking-cessation drug into pilot trials for schizophrenia?
One disease condition that is a target for nAChR agonists is mild cognitive impairment (MCI), a less severe form of cognitive dysfunction than Alzheimer' s disease. Some types of MCI may be precursors of Alzheimer' s. What methods are researchers using to clarify which types of MCI have a high risk of progression to AD?

Scope

Prospective cognitive dysfunction disease targets for nicotinic receptor agonists: Alzheimer' s disease, mild cognitive impairment, age-associated memory impairment, schizophrenia, attentiondeficit/hyperactivity disorder, Parkinson' s disease.
Biology of nicotinic receptors: structure, function, and subtypes of nAChRs; functional studies of nicotinic receptors being targeted in cognition improvement; the role of the α7 nAChR in attention; studies of the α7 nAChR in schizophrenia and Alzheimer' s disease.
Subtype-specifi c nAChR agonists in clinical development for cognitive disorders: profiles of the leading drug candidates in the nAChR agonist programs of five leading biopharmaceutical companies.
Outlook: growing corporate interest in nAChR agonists; the push toward proof-of-concept in human clinical trials; lingering concerns about addictive properties of particular subtype-specifi c nAChRs.

Executive Summary
- Strategic Considerations
- Stakeholder Implications
Introduction
Diseases Involving Cognitive Dysfunction That Are Prospective Targets for Nicotinic Receptor Agonists
- Alzheimer' s Disease
- Mild Cognitive Impairment
- Age-Associated Memory Impairment
- Schizophrenia
- Attention-Defi cit/Hyperactivity Disorder
- Parkinson' s Disease
Biology of Nicotinic Receptors
- Functional Studies of Nicotinic Receptors That Are Targets in Improvement of Cognition
- Functional Studies of nAChRs Containing the β4 Subunit Using a Subtype-Specific Drug
- Functional Studies of nAChRs Containing the β2 Subunit Using Genetic Manipulation
- A Study of the Role of the α7 nAChR in Attention
- Other Studies of the Potential Role of α7 Receptors in Schizophrenia and Alzheimer' s Disease
Subtype-Specifi c nAChR Agonists in Clinical Development for Cognitive Disorders
- Targacept/AstraZeneca' s TC-1734/AZD-3480
- CoMentis' s GTS-21
- Memory Pharmaceuticals/Roche' s MEM-3454
- EnVivo Pharmaceuticals' α7 Agonist Program
- NeuroSearch/Abbott' s Nicotinic Receptor Agonist Program
Outlook

Tables:

1. Prevalence in the Major Markets of Diseases Involving Cognitive Dysfunction That Are Targets for Nicotinic Acetylcholine Receptor Agonists, 2006
2. Properties of Neural Nicotinic Receptor Subtypes That Are Targets in Cognition
3. Select Subtype-Specific Nicotinic Receptor Agonists in Development for Cognitive Disorders