of self-medication to ameliorate some of the cognitive symptoms (► Cognitive Enhancers, ► Cognitive Enhancers: Novel Approaches) associated with disorders such as schizophrenia and ADHD. Beyond the adverse health effects of tobacco use, nicotine is not well suited as a therapeutic agent owing to its ► pharmacokinetic properties and poor toleration, especially among nonsmokers. Therefore, a number of selective nAChR ligands are being investigated as potential therapies for psychiatric and neurodegenera-tive disorders (Cincotta et al. 2008; Rusted et al. 2000).
The largest effort has centered on the a4b2 and a7 nAChRs. These subtypes are the most prevalent among brain nAChRs; they influence cognitive function in preclinical models (► Rodent Tests of Cognition) and have been associated with both psychiatric and neurodegener-ative disorders. However, recent data suggest that ligands targeting a6* nAChRs may be useful pharmacotherapies for diseases involving dopamine dysfunction.
The following sections address the major psychiatric and neurodegenerative disease areas, where nicotinic ligands have been proposed and/or tested for clinical benefit. It should be noted that the physiologic roles of individual nAChR subtypes is highly complex and far from being comprehensively understood. In addition, disease state and ligand exposure can substantially alter the number and type of nicotinic receptors expressed in various brain regions. Given these complexities, it is likely that ligands targeting an individual nAChR subtype may be beneficial for more than one disease.
Alzheimer's Disease ► Alzheimer's disease (AD) is characterized by the accumulation of neuritic ► plaques, ► neurofibrillary tangles, neuronal loss, and progressive deterioration of memory and cognitive function. Decreased levels of a4b2 nAChRs have been correlated with disease progression. This relationship, coupled with the importance of a4b2 nAChRs in cognitive function, has made this receptor subtype an attractive therapeutic target for AD, and several selective compounds have advanced to clinical trials. As the other major nAChR in the mammalian brain, the a7 receptor has also been the focus of extensive preclinical research. Activation of a7 nAChRs has been linked to cognitive enhancement, and disruption of a7 nAChR gene expression or function impairs cognitive performance and attention. Substantial drug discovery and development efforts with a7 nAChR agonists as potential treatment methods for impaired cognition in neurodegenerative diseases are ongoing.
Ispronicline (TC-1734 or AZD-3480; Fig. 6), an a4b2-selective partial agonist, significantly improved several cognitive measures for ► attention and ► episodic memory after 10 days of treatment in healthy volunteers, and induced ► Electroencephalography patterns associated with increased attention and vigilance. Similarly, isproni-cline improves cognitive function in elderly subjects with age-associated memory impairment. Initial reports on the efficacy of ispronicline in patients with AD have been mixed, but improvements in some endpoints, such as the "Mini-Mental State Examination,'' have been reported.
The selective a4b2 nAChR agonist ABT-418 (Fig. 7) demonstrates positive effects in attention and in a
► delayed matching-to-sample task performance in aged monkeys. Transdermal application in patients with AD results in dose-dependent improved ► verbal learning,
► memory, and reaction time, some of which are qualitatively and quantitatively similar to those seen in acute
Nicotinic Agonists and Antagonists. Fig. 7. Structures of nAChR ligands discussed for cognitive defects (Alzheimer's disease (AD), schizophrenia, and attention-deficit/hyperactivity disorder (ADHD)) and neuroprotection for neurodegenerative diseases (Parkinson's disease (PD)).
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