Defense Date


Document Type


Degree Name

Master of Science


Pharmaceutical Sciences

First Advisor

Małgorzata Dukat


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.


© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

July 2012