Honors Theses
Date of Award
2018
Document Type
Undergraduate Thesis
Department
Biomolecular Sciences
First Advisor
John Rimoldi
Relational Format
Dissertation/Thesis
Abstract
Cannabinoid (CB) receptors are validated drug targets in the endocannabinoid signaling system associated with a number of human pathologies, and the development of novel and selective small molecule CB ligands is warranted. A lead molecule HL-010, a member of the 4H-thieno[3,2-b]pyrrole-5-carboxamide class of compounds, was previously identified through CB homology modeling and virtual screening protocols as a potential high affinity ligand for cannabinoid receptors. Validation of the in silico data was realized with the evaluation of both CB1 and CB2 receptor binding and functional activity assessment: HL-010 was found to be a potent (~10 nM) and selective CB2 receptor agonist with more than 100-fold selectivity over CB1 receptors. Unfortunately, its high lipophilicity limited its aqueous solubility, and prevented further evaluation in animal models. The bioisostere, RS-DFA-6-2 containing the 4H-furo[3,2-b]pyrrole-5-carboxamide scaffold, was synthesized and preliminary data showed similar CB2 binding affinity (~18 nM) with modest selectivity (40 fold) compared to HL-010, with slightly improved aqueous solubility. This thesis research discloses the design and synthesis of four additional analogs modified at the carboyxamide group (7a-d) using RS-DFA-6-2 as the parent scaffold. These compounds were tested against both CB receptor and opioid receptors using established radioligand displacement assays. Additionally, compound 7a was determined to be a CB2 agonist based on functional assay data.
Recommended Citation
Thrash, Mary Paige, "Design and Synthesis of Novel Cannabinoid Receptor Modulators" (2018). Honors Theses. 665.
https://egrove.olemiss.edu/hon_thesis/665
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