Design, synthesis and biological evaluation of GPR55 agonists and resorcylic acid lactone-based analogues as TAK-1 inhibi

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Lara Alfakhouri (Creator)
The University of North Carolina at Greensboro (UNCG )
Web Site:
Mitchell Croatt

Abstract: GPR55 is a potential target for treating various illnesses. Inhibition of this membrane-bound G protein-coupled receptor may potentially alleviate inflammatory and neuropathic pain and treat osteoporosis and cancer. Radiolabelling of a potent and selective ligand will aid in establishing the physiological roles and pharmacology of the receptor. High throughput screening presented a hit that was used to design, based on a constructed homology model, and synthesize various analogues. The structure activity relationships inferred from the tested analogues will help in refinement of the homology model and design future analogues. (5Z)-7-Oxozeanol and related analogues were isolated and screened to explore their activity as TAK-1 inhibitors. Seven analogues were synthesized and eight natural products isolated that examined the role that different areas of the molecule contribute to TAK-1 inhibition. A novel nonaromatic difluoro-derivative was synthesized that had similar potency compared to the lead. This is the first example of a nonaromatic compound in this class to have TAK-1 inhibition. Covalent docking for the isolated and synthesized analogues was carried out and found a strong correlation between the observed activities and the calculated binding.

Additional Information

Language: English
Date: 2015
5Z-7-Oxozeaenol, Beta-arrestin, GPR55, Isothiocyanate, Selectfluor, TAK-1
G proteins $x Receptors $x Research

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