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Novel AMTB chimeric analogs as antagonists of the cold menthol receptor TRPM8

Patel, Smith (2024) Novel AMTB chimeric analogs as antagonists of the cold menthol receptor TRPM8. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

TRPM8, also known as the cold menthol receptor, is a calcium-permeable ion channel
of the transient receptor potential (TRP) channel superfamily that is second only to voltage-gated
potassium channels. TRPM8 knockout mice show no reaction to decreases in environmental
temperature and exhibit minimal sensitivity to cold stimuli after traumatic nerve injury. Existing
TRPM8 antagonists can alleviate pain but disrupt core body temperature regulation. We
hypothesize that the activation of human TRPM8 by ligands and environmental cold occurs in a
different part of the channel than the region responsible for TRPM8 activation involved in
thermoregulation, such as maintaining core body temperature or responding to hypothermia. Our
approach is to generate novel, mode-selective antagonists capable of performing strong, anchoring
interactions in the common binding site sensitive to chemical and environmental cold stimuli, with
chimeric molecules of the TRPM8 antagonist AMTB and our existing VBJ series, to reverse cold
hypersensitivity in the absence of a thermoregulatory effect. Here, we report a series of AMTB
VBJ chimeric analogs that inhibit chemical (icilin)-induced responses at human TRPM8 in a dose
dependent manner. Compounds 6a, 6e, and 6i inhibit icilin-stimulated responses with IC50 values
of 4.4 ± 0.8 µM, 3.3 ±1.8 µM, and 2.6 ± 2.1 µM, respectively. Compounds 6a and 6e possess
optimum logD values and in-vitro T1/2 values of 18.2 and 23.3 min in mouse liver microsomes.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Patel, Smithsjp139@pitt.edusjp139
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorJournigan, Velvetvea22@pitt.eduvea22
Committee ChairJun, Jaden Junghojjj46@pitt.edujjj46
Committee MemberZhang, Weiweizhang@pitt.eduweizhang
Date: 7 August 2024
Date Type: Publication
Defense Date: 19 July 2024
Approval Date: 7 August 2024
Submission Date: 26 July 2024
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 105
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: TRPM8 channel, antagonists, thermoregulatory effect
Date Deposited: 07 Aug 2024 12:20
Last Modified: 07 Aug 2024 12:20
URI: http://d-scholarship.pitt.edu/id/eprint/46845

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  • Novel AMTB chimeric analogs as antagonists of the cold menthol receptor TRPM8. (deposited 07 Aug 2024 12:20) [Currently Displayed]

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