Discovery of Novel Negative Allosteric Modulators of Neuronal Nicotinic Acetylcholine Receptors: Implications in the Treatment of Addiction and Other Neurological Disorders
Boyd, R. Thomas
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Publisher:The Ohio State University
Series/Report no.:The Ohio State University. School of Biomedical Science Honors Theses; 2010
Neuronal nicotinic acetylcholine receptors (nAChRs) represent a large family of membrane receptors that are involved in numerous neurotransmitter systems throughout the brain. For this reason, nAChRs are implicated in many neurological diseases involving various brain pathways including but not limited to addiction, Alzheimer's disease, Parkinson's disease, schizophrenia, and autism. A major conundrum in nAChR research is the development of agents that selectively target receptor subtypes. This is important because contemporary therapies targeting specific nAChRs are associated with a myriad of neurological side effects due to their off target interaction with other nAChRs. Our laboratory has identified a class of compounds targeting a novel allosteric site on nAChRs. This site is unique for each subtype as the amino acid residues within the binding pocket are different across subtypes. Utilizing Structure Activity Relationships (SAR) and computational modeling we are identifying novel compounds that target this site. The end goal is to identify a potent and selective negative allosteric modulator of nAChRs. Specifically, our laboratory is investigating compounds targeting the alpha4beta2 subtype. The alpha4beta2 nAChR is implicated in the development of addiction following exposure to drugs of abuse such as nicotine. Therefore, a drug selectively targeting this receptor would be an effective smoking cessation therapy. In addition, the identification of an effective modulator of the alpha4beta2 receptor would provide further evidence that our approach can be utilized for any nAChR subtype for the development of potent and selective drugs to treat neurological disease.