Date of Award
School of Pharmacy
Type of Degree
Dr. Velvet Journigan, Committee Chairperson
Dr. Timothy E. Long
Dr. John Markiewicz
TRP channels are the major temperature sensing receptors in the body. TRPM8 is the primary cold thermoreceptor for both innocuous cold and cold pain, and has been linked to a variety of diseases, including chemotherapy (oxaliplatin)-induced cold allodynia and chronic neuropathic pain. Antagonists of TRPM8 have been proposed as a viable therapeutic option for those disease states. Current data from our lab shows that the TRPM8 antagonist VBJ-103 is 100-fold selective for TRPM8 vs. related thermoTRP channels TRPV1 (vanilloid 1) and TRPA1 (ankyrin 1). Analogs of VBJ-103 using a structure-based drug design approach may result in changes to selectivity and antagonist potency for TRPM8. The hypothesis is that selectivity could improve by targeting a basic Arg842 residue with acidic functional groups. A nine-step synthesis was undertaken to prepare acidic analogs of VBJ-103. This work demonstrates the completed synthetic route optimization and scale-up of the initial four steps that resulted in generation of 3.7 g of a critical amine intermediate (4) consisting of cis and trans isomers, verified by 2D NMR experiments. It was determined that the racemic mixture of 5 had an IC50 of 13.68 ± 0.2 µM. Finally, two chimeric analogs of the well-known TRPM8 antagonist AMTB and our scaffolds were designed and synthesized for biological evaluation. VBJ103-AMTB chimera (vbj_2_070) has an IC50 of 0.94 ± 0.2 µM, and VBJ104TB-AMTB chimera (vbj_2_071) has an IC50 of 0.5 ± 0.1 µ
Nervous system -- Diseases -- Research.
Neurotransmitter receptors -- Research.
Neuropharmacology -- Research.
Dawley, Denise Catherine, "Structure-based design and synthesis of transient receptor potential melastatin 8 (TRPM8) ion channel ligands" (2021). Theses, Dissertations and Capstones. 1379.
Available for download on Saturday, March 10, 2029