DOI
https://doi.org/10.25772/K30N-4834
Defense Date
2012
Document Type
Thesis
Degree Name
Master of Science
Department
Pharmaceutical Sciences
First Advisor
Małgorzata Dukat
Abstract
Alpha7 Neuronal nicotinic acetylcholine receptors (nAChRs) are involved in essential physiological functions and play a role in disorders such as Alzheimer’s disease. MD-354 (3-chlorophenylguanidine; 21), the first small–molecule negative allosteric modulator (NAM) at alpha7 nAChRs, served as a lead in developing structure–activity relationships for NAMs at a7 nAChRs. MD-354 (21) also binds at 5-HT3 receptors. Analogs of MD-354 with structural features detrimental to 5-HT3 receptor affinity were evaluated in patch-clamp recordings and an aniline N-methyl analog resulted in a more potent and selective NAM than MD-354. A new N-methyl series of compounds was synthesized in which the 3-position was replaced with different substituents considering their electronic, lipophilic, and steric nature. Comparative studies were initiated to investigate whether or not the MD-354 series and the N-methyl series bind in the same manner; 3D models of the extracellular domain of human alpha7 nAChRs were developed, allosteric sites identified, and docking studies conducted.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
July 2012