Georgia State University
Klenc, Jeffrey D.
Design and Synthesis of Novel Serotonin Receptor Ligands.
Degree: PhD, Chemistry, 2010, Georgia State University
Novel and potent ligands to the serotonin7 (5-HT7) receptor have been synthesized. The synthesized compounds include a set of substituted pyrimidines which show high affinity to the 5-HT7 receptor, synthesized by previously described methods [1,2] in high yield. Comparing the affinities of substituted pyrimidines to previously calculated models [3,4] yielded new hypotheses about the nature of interaction between the pyrimidine ligands and the 5-HT7 binding site. Several new series of compounds were synthesized by various methods to validate these hypotheses, including a conjugate addition to vinylpyrimidines . These compounds include benzofurans, oximes, hydrazones, as well as a group of substituted piperazines. All series of compounds show affinity to the 5-HT7 receptor comparable to previously synthesized 5-HT7 ligands. Several of the synthesized ligands show affinity which exceeds that of currently available ligands. The synthesized compounds were evaluated quantitatively by calculating a three-dimensional quantitative structure-affinity relationship (3D-QSAR) for the 5-HT7 receptor. Evaluation of the calculated model validated qualitative assumptions about the data set as well as described regions of interaction in greater detail than previously available. These observations give further insight on the nature of ligand-binding site interactions with highly potent ligands such as 4-(3-furyl)-2-(N-methylpiperazino)pyrimidine which will lead to more potent 5-HT7 receptor ligands. Additionally, a model was calculated for affinity to the 5-HT2a receptor. Comparing this model to that calculated for affinity to the 5-HT7 receptor identified two regions which may be exploited in future sets of ligands to increase selectivity to the 5HT7 receptor.
Advisors/Committee Members: Dr. Strekowski, Dr. Germann.
Subjects/Keywords: Serotonin; 5-HT; Depression; Schizophrenia; Pyrimidine; 1-4 Addition; 3D-QSAR; Molecular modeling; 5-HT7 receptor; 5-HT7 ligands; 5-HT1a; 5-HT2a; Pharmacophore; Chemistry
to Zotero / EndNote / Reference
APA (6th Edition):
Klenc, J. D. (2010). Design and Synthesis of Novel Serotonin Receptor Ligands. (Doctoral Dissertation). Georgia State University. Retrieved from https://scholarworks.gsu.edu/chemistry_diss/50
Chicago Manual of Style (16th Edition):
Klenc, Jeffrey D. “Design and Synthesis of Novel Serotonin Receptor Ligands.” 2010. Doctoral Dissertation, Georgia State University. Accessed October 16, 2019.
MLA Handbook (7th Edition):
Klenc, Jeffrey D. “Design and Synthesis of Novel Serotonin Receptor Ligands.” 2010. Web. 16 Oct 2019.
Klenc JD. Design and Synthesis of Novel Serotonin Receptor Ligands. [Internet] [Doctoral dissertation]. Georgia State University; 2010. [cited 2019 Oct 16].
Available from: https://scholarworks.gsu.edu/chemistry_diss/50.
Council of Science Editors:
Klenc JD. Design and Synthesis of Novel Serotonin Receptor Ligands. [Doctoral Dissertation]. Georgia State University; 2010. Available from: https://scholarworks.gsu.edu/chemistry_diss/50