Design and Synthesis of Novel Cannabinoid Receptor Modulators

Thrash, Mary Paige (2018) Design and Synthesis of Novel Cannabinoid Receptor Modulators. Undergraduate thesis, under the direction of John Rimoldi from BioMolecular Sciences, The University of Mississippi.

Text Honors Thesis Mary Thrash final official.pdf Restricted to Repository staff only until 31 May 2019. Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (2MB)

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.

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