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Lenham, Rhianna (2025) Development of novel therapeutic agents designed to enhance insulin secretion through activation of the trace amine-associated receptor 1 (TAAR1). PhD thesis, University of Nottingham.

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Abstract

Produced in the pancreas, insulin is widely considered the most important hormone involved in metabolic homeostasis. Diabetes mellitus (DM) is a chronic metabolic disease affecting 537 million people worldwide which results from a defect in insulin action, secretion, or both. Over time, existing antihyperglycemic treatments designed to control type 2 DM (T2DM) typically become ineffective due to changes in disease progression including weight gain and increased insulin resistance, highlighting the importance for the continued development of new therapeutic agents which exert their effects through diverse/ novel mechanisms.

Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor located in the brain, stomach, intestines and pancreatic β-cells which has roles in mediating neurodegenerative and metabolic disorders. Although most of the existing research into TAAR1 agonists has focused on their role within the central nervous system for application in schizophrenia treatments, studies have identified activation of pancreatic TAAR1 enhances insulin secretion, thus TAAR1 is a promising target for novel antihyperglycemic treatments for T2DM.

This thesis reports the rational design, synthesis and pharmacological evaluation of a series of ligands intended to exhibit a peripherally restricted TAAR1 agonist profile, based on N-((1H-imidazol-4-yl)methyl)-4-chloro-N-isopropylaniline (RO5073012, 59), as part of a structure activity relationship study. The analogues are computationally predicted to be substrates of the P-glycoprotein transporter and experimentally predicted to have low blood brain barrier permeability through immobilised artificial membrane reversed-phase high performance liquid chromatography, preventing the likelihood of inducing potential undesired on-target effects. The data obtained from high range rat insulin enzyme-linked immunosorbent assays (Mercodia) shows that the novel analogues enhance insulin secretion in control and glucolipotoxicity conditions designed to mimic an environment typically associated with patients with poorly controlled T2DM. We also demonstrate that one compound, N-((1H-imidazol-2-yl)methyl)-4-chloro-N-isopropylaniline (76c), upregulates the secondary messenger cyclic adenosine monophosphate (cAMP) using the cAMP select ELISA (Cayman Chemical). This suggests 76c mediates its therapeutic effects via TAAR1 thus indicating a potential role for these molecules as novel therapeutic agents in the treatment of T2DM.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Turner, Mark Mistry, Shailesh Laughton, Charles
Keywords:	insulin, metabolic homeostasis, receptors
Subjects:	Q Science > QP Physiology > QP1 Physiology (General) including influence of the environment Q Science > QP Physiology > QP501 Animal biochemistry
Faculties/Schools:	UK Campuses > Faculty of Science > School of Biosciences
Item ID:	80607
Depositing User:	Lenham, Rhianna
Date Deposited:	15 May 2025 10:55
Last Modified:	15 May 2025 10:55
URI:	https://eprints.nottingham.ac.uk/id/eprint/80607

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