Small Molecule Drug Discovery at the Glucagon-Like Peptide-1 Receptor

Translational Science and Technologies, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Experimental Diabetes Research (Impact Factor: 4.33). 02/2012; 2012(7329):709893. DOI: 10.1155/2012/709893
Source: PubMed


The therapeutic success of peptide glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus has inspired discovery efforts aimed at developing orally available small molecule GLP-1 receptor agonists. Although the GLP-1 receptor is a member of the structurally complex class B1 family of GPCRs, in recent years, a diverse array of orthosteric and allosteric nonpeptide ligands has been reported. These compounds include antagonists, agonists, and positive allosteric modulators with intrinsic efficacy. In this paper, a comprehensive review of currently disclosed small molecule GLP-1 receptor ligands is presented. In addition, examples of "ligand bias" and "probe dependency" for the GLP-1 receptor are discussed; these emerging concepts may influence further optimization of known molecules or persuade designs of expanded screening strategies to identify novel chemical starting points for GLP-1 receptor drug discovery.

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Available from: Ana Belén Bueno, Nov 11, 2014
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    • "While the functional effect of this truncation is well characterized, the structural consequences are not fully understood. In addition, many small molecule GLP-1R agonists have been reported recently [4]. Mass spectrometric-based quantitation of protein amide hydrogen exchange for deuterons from heavy water buffers can detect perturbations in a protein's conformational ensemble in response to ligand binding [15], [16]. "
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    ABSTRACT: Activation of the glucagon-like peptide-1 receptor (GLP-1R) in pancreatic β-cells potentiates insulin production and is a current therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). Like other class B G protein-coupled receptors (GPCRs), the GLP-1R contains an N-terminal extracellular ligand binding domain. N-terminal truncations on the peptide agonist generate antagonists capable of binding to the extracellular domain, but not capable of activating full length receptor. The main objective of this study was to use Hydrogen/deuterium exchange (HDX) to identify how the amide hydrogen bonding network of peptide ligands and the extracellular domain of GLP-1R (nGLP-1R) were altered by binding interactions and to then use this platform to validate direct binding events for putative GLP-1R small molecule ligands. The HDX studies presented here for two glucagon-like peptide-1 receptor (GLP-1R) peptide ligands indicates that the antagonist exendin-4[9-39] is significantly destabilized in the presence of nonionic detergents as compared to the agonist exendin-4. Furthermore, HDX can detect stabilization of exendin-4 and exendin-4[9-39] hydrogen bonding networks at the N-terminal helix [Val19 to Lys27] upon binding to the N-terminal extracellular domain of GLP-1R (nGLP-1R). In addition we show hydrogen bonding network stabilization on nGLP-1R in response to ligand binding, and validate direct binding events with the extracellular domain of the receptor for putative GLP-1R small molecule ligands.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "It would be interesting to know whether small molecules produce antinociception by activating the GLP-1Rs with a full intrinsic efficacy. As peptidic exenatide and GLP-1 are not orally-active, the development of orally-available, non-peptidic GLP-1R agonists has been an active, although as yet unfruitful, area of research for both anti-diabetic drugs and analgesics (Wang et al., 2010; Willard et al., 2012). As exenatide and GLP-1 cannot readily cross the blood brain barrier, orally-available GLP-1R agonists with the ability to penetrate the central nervous system, leading to more specific, efficacious analgesics, must be developed. "
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    ABSTRACT: We recently discovered that the activation of the spinal glucagon-like peptide-1 receptors (GLP-1Rs) by the peptidic agonist exenatide produced antinociception in chronic pain. We suggested that the spinal GLP-1Rs are a potential target molecule for the management of chronic pain. This study evaluated the antinociceptive activities of geniposide, a presumed small molecule GLP-1R agonist. Geniposide produced concentration-dependent, complete protection against hydrogen peroxide-induced oxidative damage in PC12 and HEK293 cells expressing rat and human GLP-1Rs, but not in HEK293T cells that do not express GLP-1Rs. The orthosteric GLP-1R antagonist exendin(9-39) right-shifted the concentration-response curve of geniposide without changing the maximal protection, with identical pA2 values in both cell lines. Subcutaneous and oral geniposide dose-dependently blocked the formalin-induced tonic response but not the acute flinching response. Subcutaneous and oral geniposide had maximum inhibition of 72% and 68%, and ED50s of 13.1 and 52.7 mg/kg, respectively. Seven days of multidaily subcutaneous geniposide and exenatide injections did not induce antinociceptive tolerance. Intrathecal geniposide induced dose-dependent antinociception, which was completely prevented by spinal exendin(9-39), siRNA/GLP-1R and cyclic AMP/PKA pathway inhibitors. The geniposide iridoid analogs geniposidic acid, genipin methyl ether, 1,10-anhydrogenipin, loganin and catalpol effectively inhibited hydrogen peroxide-induced oxidative damage and formalin pain in an exendin(9-39)-reversible manner. Our results suggest that geniposide and its iridoid analogs produce antinociception during persistent pain by activating the spinal GLP-1Rs and that the iridoids represented by geniposide are orthosteric agonists of GLP-1Rs that function similarly in humans and rats and presumably act at the same binding site as exendin(9-39).
    Full-text · Article · Apr 2014 · Neuropharmacology
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    • "Currently, approved therapeutics acting at the GLP-1R are peptide-based; however, there is substantial interest in development of small molecule drugs. In recent years, an increasing number of reports have shown discovery of structurally diverse small molecule agonists of the GLP-1R (Willard et al., 2012a). These include (but are not limited to) a series of quinoxalines, the best characterized being Compound 2 (6.7-dichloro-2-methylsulfonyl-3- tert-butylaminoquinoxaline), a series of pyrimidines, the best characterized being BETP (4-(3-benzyloxyphenyl)- 2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine), substituted cyclobutanes such as Boc5 (1,3-bis [[4-(tert-butoxy-carbonylamino) benzoyl]amino]-2,4-bis[3-methoxy-4-(thiophene-2-carbonyloxy)- phenyl]cyclobutane-1,3-dicarboxylic acid), and a series of compounds reported in patents by Transtech Pharma. "
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    ABSTRACT: The glucagon-like peptide-1 receptor (GLP-1R) is a major therapeutic target for the treatment of type 2 diabetes due to its role in glucose homeostasis. Despite the availability of peptide based GLP-1R drugs for treatment of this disease, there is great interest in developing small molecules that can be administered orally. The GLP-1R system is complex, with multiple endogenous and clinically used peptide ligands that exhibit different signalling biases at this receptor. This study revealed that small molecule ligands acting at this receptor are differentially biased to peptide ligands and also from each other with respect to the signalling pathways that they activate. Furthermore, allosteric, small molecule ligands were able to induce bias in signalling mediated by orthosteric ligands. This was dependent on both the orthosteric and allosteric ligand as no two allosteric-orthosteric ligand pairs could induce the same signalling profile. We highlight the need to profile compounds across multiple signalling pathways and in combination with multiple orthosteric ligands in systems such as the GLP-1R where more than one endogenous ligand exists. In the context of pleiotropical coupling of receptors and the interplay of multiple pathways leading to physiological responses, profiling of small molecules in this manner may lead to a better understanding of the physiological consequences of biased signalling at this receptor. This could enable the design and development of improved therapeutics that have the ability to fine-tune receptor signalling leading to beneficial therapeutic outcomes while reducing side effect profiles.
    Full-text · Article · Jan 2013 · Molecular pharmacology
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