New trisubstituted 1,2,4-triazoles as ghrelin receptor antagonists

Blayo, Anne‐Laure; Maingot, Mathieu; Aicher, Babette; M’Kadmi, Céline; Schmidt, Péter; Müller, Gilbert; Teifel, Michael; Günther, E; Gagne, Didier; Denoyelle, Séverine; Martinez, Jean; Fehrentz, Jean‐Alain

doi:10.1016/j.bmcl.2014.11.031

Cited by 7 publications

(7 citation statements)

References 26 publications

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“…An example of another ghrelin receptor ligand known as JMV3018 was also able to partially activate the Gαq-protein signaling pathway but unable to recruit β-Arrestin [ 57 ]. In addition, recent studies including a study carried out in our laboratory [ 58 ] have demonstrated that GHS-R1a receptor ligands display signaling bias with functional selectivity for specific downstream signaling pathways [ 22 , 59 , 60 , 61 , 62 ]. Indeed, several different active conformations of the GHS-R1a receptor may exist [ 42 ], with biased ligands able to induce a receptor conformation that preferentially activates only G protein-mediated or β-arrestin-mediated downstream signaling [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

Quinolones Modulate Ghrelin Receptor Signaling: Potential for a Novel Small Molecule Scaffold in the Treatment of Cachexia

Torres‐Fuentes

Pastor-Cavada

Cano

et al. 2018

IJMS

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Cachexia is a metabolic wasting disorder characterized by progressive weight loss, muscle atrophy, fatigue, weakness, and appetite loss. Cachexia is associated with almost all major chronic illnesses including cancer, heart failure, obstructive pulmonary disease, and kidney disease and significantly impedes treatment outcome and therapy tolerance, reducing physical function and increasing mortality. Current cachexia treatments are limited and new pharmacological strategies are needed. Agonists for the growth hormone secretagogue (GHS-R1a), or ghrelin receptor, prospectively regulate the central regulation of appetite and growth hormone secretion, and therefore have tremendous potential as cachexia therapeutics. Non-peptide GHS-R1a agonists are of particular interest, especially given the high gastrointestinal degradation of peptide-based structures, including that of the endogenous ligand, ghrelin, which has a half-life of only 30 min. However, few compounds have been reported in the literature as non-peptide GHS-R1a agonists. In this paper, we investigate the in vitro potential of quinolone compounds to modulate the GHS-R1a in both transfected human cells and mouse hypothalamic cells. These chemically synthesized compounds demonstrate a promising potential as GHS-R1a agonists, shown by an increased intracellular calcium influx. Further studies are now warranted to substantiate and exploit the potential of these novel quinolone-based compounds as orexigenic therapeutics in conditions of cachexia and other metabolic and eating disorders.

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Section: Discussionmentioning

confidence: 99%

Quinolones Modulate Ghrelin Receptor Signaling: Potential for a Novel Small Molecule Scaffold in the Treatment of Cachexia

Torres‐Fuentes

Pastor-Cavada

Cano

et al. 2018

IJMS

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“…Growth hormone secretagogues (GHSs), able to interact with the GHSR1a receptor, have been regarded as an alternative to support diagnostics and to treat diseases related to GH deficiency due to their ability to release this hormone in the body. [1,2] A widespread variety of compounds, including growth hormone releasing peptides (GHRPs) [1][2][3][4][5][6] and non-peptidic compounds [5,7,8] have been developed by the pharmaceutical industry. [9] However, so far only the peptide GHRP-2 (also known as Pralmorelin) has been clinically tested and approved in Japan for diagnostic purposes, while a few other GHSs are still in different stages of development.…”

Section: Introductionmentioning

confidence: 99%

“…Studies on the structure of ghrelin itself and truncated ghrelin analogues that maintain the activity at receptor level have been carried out. [5,23,24] Also, pharmaceutical companies and other researchers have investigated a homologous series of nonpeptidic [8,[25][26][27][28][29] or peptidic [4,24,[30][31][32] compounds. However, as some specific GHRPs such as GHRP-1, GHRP-2, GHRP-4, GHRP-5, GHRP-6, Hexarelin, or Alexamorelin are among the most available to cheating athletes, and bear a common core chemical structure, some further specific insight into their particular structure-activity relationship seems appropriate.…”

Section: Introductionmentioning

confidence: 99%

Structure‐activity relationship for peptídic growth hormone secretagogues

Ferro

Krotov²,

Zvereva³

et al. 2016

Drug Testing and Analysis

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Growth hormone releasing peptides (GHRPs) could be widely used by cheating athletes because they produce growth hormone (GH) secretion, so may generate an ergogenic effect in the body. Knowledge of the essential amino acids needed in GHRP structure for interaction with the target biological receptor GHSR1a, the absorption through different administration routes, and the maintenance of pharmacological activity of potential biotransformation products may help in the fight against their abuse in sport. Several GHRPs and truncated analogues with the common core Ala-Trp-(D-Phe)-Lys have been studied with a radio-competitive assay for the GHSR1a receptor against the radioactive natural ligand ghrelin. Relevant chemical modifications influencing the activity for positions 1, 2, 3, and 7 based on the structure aa-aa-aa-Ala-Trp-(D-Phe)-Lys have been obtained. To test in vivo the applicability of the activities observed, the receptor assay activity in samples from excretion studies performed after nasal administration of GHRP-1, GHRP-2, GHRP-6, Hexarelin, and Ipamorelin was confirmed. Overall results obtained allow to infer structure-activity information for those GHRPs and to detect GHSR1a binding (intact GHRPs plus active metabolites) in excreted urines. Copyright © 2016 John Wiley & Sons, Ltd.

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“…The 1,2,4-triazoles are considered an important nucleus that is associated with numerous biological activities, such as herbicidal [4][5][6], antifungal [7][8][9], antiviral [10], GHS-R1a ghrelin receptor [11], antimicrobial [12], anticancer [13], anticonvulsant [14], and antitubercular activities [15]. In addition, Diniconazole, Triadimefon, Triadimenol, Flusilazole, Fluconazole, Itraconazole, which have a 1,2,4-triazole moiety, appear to be very effective.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Crystal Structure, DFT Study and Antifungal Activity of 4-(5-((4-Bromobenzyl) thio)-4-Phenyl-4H-1,2,4-Triazol-3-yl)pyridine

Zhai

Yang

et al. 2015

Crystals

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Abstract:The title compound 4-(5-((4-bromobenzyl)thio)-4-phenyl-4H-1,2,4-triazol-3-yl)pyridine (C 20 H 15 BrN 4 S) was synthesized, and its structure was confirmed by 1 H NMR, MS and elemental analyses and single-crystal X-ray structure determination. It crystallizes in the triclinic space group P-1 with a = 7.717(3), b = 9.210(3), c = 13.370(5) Å, α = 80.347(13), β = 77.471(13), γ = 89.899(16)˝, V = 913.9(6) Å 3 , Z = 2 and R = 0.0260 for 3145 observed reflections with I > 2σ(I). A Density functional theory (DFT) (B3LYP/6-31G) calculation of the title molecule was carried out. The full geometry optimization was carried out using a 6-31G basis set, and the frontier orbital energy. Atomic net charges are discussed. Calculated bond lengths and bond angles were found to differ from experimental values, and the compound exhibits moderate antifungal activity.

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New trisubstituted 1,2,4-triazoles as ghrelin receptor antagonists

Cited by 7 publications

References 26 publications

Quinolones Modulate Ghrelin Receptor Signaling: Potential for a Novel Small Molecule Scaffold in the Treatment of Cachexia

Quinolones Modulate Ghrelin Receptor Signaling: Potential for a Novel Small Molecule Scaffold in the Treatment of Cachexia

Structure‐activity relationship for peptídic growth hormone secretagogues

Synthesis, Crystal Structure, DFT Study and Antifungal Activity of 4-(5-((4-Bromobenzyl) thio)-4-Phenyl-4H-1,2,4-Triazol-3-yl)pyridine

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