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Non-peptide agonists and positive allosteric modulators of glucagon-like peptide-1 receptors: Alternative approaches for treatment of Type 2 diabetes.

ABSTRACT: Glucagon-like peptide-1 (GLP-1) receptors belong to the pharmaceutically important Class B family of GPCRs and are involved in many biologically significant signalling pathways. Its incretin peptide ligand GLP-1 analogues are effective treatments for Type 2 diabetes. Although developing non-peptide low MW drugs targeting GLP-1 receptors remains elusive, considerable progress has been made in discovering non-peptide agonists and positive allosteric modulators (PAMs) of GLP-1 receptors with demonstrated efficacy. Many of these compounds induce biased signalling in GLP-1 receptor-mediated functional pathways. High-quality structures of GLP-1 receptors in both inactive and active states have been reported, revealing detailed molecular interactions between GLP-1 receptors and non-peptide agonists or PAMs. These progresses raise the exciting possibility of developing non-peptide drugs of GLP-1 receptors as alternative treatments for Type 2 diabetes. The insight into the interactions between the receptor and the non-peptide ligand is also useful for developing non-peptide ligands targeting other Class B GPCRs. LINKED ARTICLES: This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc.

SUBMITTER: Malik F

PROVIDER: S-EPMC8820177 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Non-peptide agonists and positive allosteric modulators of glucagon-like peptide-1 receptors: Alternative approaches for treatment of Type 2 diabetes.

Malik Faisal F Li Zhijun Z

British journal of pharmacology 20210419 4

Glucagon-like peptide-1 (GLP-1) receptors belong to the pharmaceutically important Class B family of GPCRs and are involved in many biologically significant signalling pathways. Its incretin peptide ligand GLP-1 analogues are effective treatments for Type 2 diabetes. Although developing non-peptide low MW drugs targeting GLP-1 receptors remains elusive, considerable progress has been made in discovering non-peptide agonists and positive allosteric modulators (PAMs) of GLP-1 receptors with demons ...[more]

PMID: 33724441

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Project description:The N-methyl-D-aspartate (NMDA) receptor family regulates various central nervous system functions, such as synaptic plasticity. However, hypo- or hyperactivation of NMDA receptors is critically involved in many neurological and psychiatric conditions, such as pain, stroke, epilepsy, neurodegeneration, schizophrenia, and depression. Consequently, subtype-selective positive and negative modulators of NMDA receptor function have many potential therapeutic applications not addressed by currently available compounds. We have identified allosteric modulators with several novel patterns of NMDA receptor subtype selectivity that have a novel mechanism of action. In a series of carboxylated naphthalene and phenanthrene derivatives, compounds were identified that selectively potentiate responses at GluN1/GluN2A [e.g., 9-iodophenanthrene-3-carboxylic acid (UBP512)]; GluN1/GluN2A and GluN1/GluN2B [9-cyclopropylphenanthrene-3-carboxylic acid (UBP710)]; GluN1/GluN2D [3,5-dihydroxynaphthalene-2-carboxylic acid (UBP551)]; or GluN1/GluN2C and GluN1/GluN2D receptors [6-, 7-, 8-, and 9-nitro isomers of naphth[1,2-c][1,2,5]oxadiazole-5-sulfonic acid (NSC339614)] and have no effect or inhibit responses at the other NMDA receptors. Selective inhibition was also observed; UBP512 inhibits only GluN1/GluN2C and GluN1/GluN2D receptors, whereas 6-bromo-2-oxo-2H-chromene-3-carboxylic acid (UBP608) inhibits GluN1/GluN2A receptors with a 23-fold selectivity compared with GluN1/GluN2D receptors. The actions of these compounds were not competitive with the agonists L-glutamate or glycine and were not voltage-dependent. Whereas the N-terminal regulatory domain was not necessary for activity of either potentiators or inhibitors, segment 2 of the agonist ligand-binding domain was important for potentiating activity, whereas subtype-specific inhibitory activity was dependent upon segment 1. In terms of chemical structure, activity profile, and mechanism of action, these modulators represent a new class of pharmacological agents for the study of NMDA receptor subtype function and provide novel lead compounds for a variety of neurological disorders.

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Non-peptide agonists and positive allosteric modulators of glucagon-like peptide-1 receptors: Alternative approaches for treatment of Type 2 diabetes.

Publications

Non-peptide agonists and positive allosteric modulators of glucagon-like peptide-1 receptors: Alternative approaches for treatment of Type 2 diabetes.

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