-
Endocrine Journal Nov 2022The thyrotropin receptor (TSHR) plays critical roles in thyroid growth and function and in the pathogenesis of several thyroid diseases including Graves' hyperthyroidism... (Review)
Review
The thyrotropin receptor (TSHR) plays critical roles in thyroid growth and function and in the pathogenesis of several thyroid diseases including Graves' hyperthyroidism and ophthalmopathy, non-autoimmune hyperthyroidism and thyroid cancer. Several low-molecular weight compounds (LMWCs) and anti-TSHR monoclonal antibodies (mAbs) with receptor antagonistic and inverse agonistic activities have been reported. The former binds to the pocket formed by the receptor transmembrane bundle, and the latter to the extracellular TSH binding site. Both are effective inhibitors of TSH/thyroid stimulating antibody-stimulated cAMP and/or hyaluronic acid production in TSHR-expressing cells. Anti-insulin-like growth factor 1 inhibitors are also found to inhibit TSHR signaling. Each agent has advantages and disadvantages; for example, mAbs have a higher affinity and longer half-life but are more costly than LMWCs. At present, mAbs appear most promising, yet the development of more efficacious LMWCs is desirable. These agents are anticipated to be efficacious not only for the above-mentioned diseases but also for resistance to thyroid hormone and have utility for thyroid cancer radionuclide scintigraphy/therapy as a new theranostic.
Topics: Humans; Antibodies, Monoclonal; Autoantibodies; Hyperthyroidism; Immunoglobulins, Thyroid-Stimulating; Receptors, G-Protein-Coupled; Receptors, Thyrotropin; Thyroid Diseases; Thyroid Neoplasms; Thyrotropin
PubMed: 36171093
DOI: 10.1507/endocrj.EJ22-0391 -
Life Sciences Mar 2021The present study aimed to disclose a potent and selective GPR120 agonist LXT34 and its anti-diabetic effects.
AIMS
The present study aimed to disclose a potent and selective GPR120 agonist LXT34 and its anti-diabetic effects.
MAIN METHODS
Calcium mobilization assay was used to measure the agonistic potency and selectivity of LXT34 in GPR120 or GPR40-overexpression Chinese hamster ovary (CHO) cells. Glucagon-like peptide-1 (GLP-1) release and glucose-stimulated insulin secretion (GSIS) were evaluated in human colonic epithelial cell line NCI-H716 and mouse insulinoma cell line MIN6 by enzyme-linked immunosorbent assay (ELISA), respectively. The anti-inflammatory effect was determined in lipopolysaccharide (LPS)-induced murine macrophage cell line RAW264.7. Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were performed to assess the anti-diabetic effects of LXT34 in db/db mice, and chronic inflammation in liver and adipose tissues were investigated using histomorphology, immunoblot and gene expression analysis.
KEY FINDINGS
LXT34 was a potent GPR120 agonist with negligible activity toward human and mouse GPR40. LXT34 could potentiate GSIS and suppress LPS-induced inflammation in macrophages. LXT34 not only markedly improved glucose tolerance and insulin resistance, but also distinctly reduced macrophages infiltration, pro-inflammatory cytokines expression and JNK phosphorylation of both liver and adipose tissues in db/db mice.
SIGNIFICANCE
LXT34, a novel and potent GPR120-selective agonist, showed beneficial effects on improving glucose homeostasis in obesity-related type 2 diabetes.
Topics: Adipose Tissue; Animals; Chronic Disease; Glucagon-Like Peptide 1; Glucose; Inflammation; Insulin Resistance; Insulin Secretion; Lipopolysaccharides; Liver; Mice; Mice, Inbred C57BL; RAW 264.7 Cells; Receptors, G-Protein-Coupled
PubMed: 33450256
DOI: 10.1016/j.lfs.2021.119029 -
Basic & Clinical Pharmacology &... Jun 2020G protein-coupled receptors (GPCRs) constitute the largest family of receptors and membrane proteins in the human genome with ~800 members of which half are olfactory.... (Review)
Review
G protein-coupled receptors (GPCRs) constitute the largest family of receptors and membrane proteins in the human genome with ~800 members of which half are olfactory. GPCRs are activated by a very broad range of endogenous signalling molecules and are involved in a plethora of physiological functions. All GPCRs contain a transmembrane domain, consisting of a bundle of seven α-helices spanning the cell membrane, and forming the majority of the known ortho- or allosteric ligand binding sites. Due to their many physiological functions and the accessible and druggable transmembrane pocket, GPCRs constitute the largest family of drug targets mediating the actions of 34% of currently marketed drugs. GPCRs activate one or more of the four G protein families (G , G , G and G ) and/or ß-arrestin. About a third of the non-olfactory GPCRs are referred to as orphan receptors which means that their endogenous agonist(s) have not yet been found or firmly established. In this MiniReview, we focus on the orphan GPR139 receptor, for which the aromatic amino acids L-Trp and L-Phe as well as ACTH/α-MSH-related peptides have been proposed as endogenous agonists. GPR139 has been reported to activate several G protein pathways of which G is the primary one. The receptor shows the highest expression in the striatum, thalamus, hypothalamus, pituitary and habenula of the human, rat and mouse CNS. We review the surrogate agonists and antagonists that have been published as well as the agonist pharmacophore and binding site. Finally, the putative physiological functions and therapeutic potential are outlined.
Topics: Animals; Brain; Humans; Mice; Nerve Tissue Proteins; Rats; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 31132229
DOI: 10.1111/bcpt.13263 -
Indian Journal of Cancer Mar 2022Androgen deprivation therapy (ADT) using gonadotropin-releasing hormone agonist (s) (GnRH-A) remains the backbone of advanced prostate cancer treatment. In this review,... (Review)
Review
Androgen deprivation therapy (ADT) using gonadotropin-releasing hormone agonist (s) (GnRH-A) remains the backbone of advanced prostate cancer treatment. In this review, we assessed the efficacy, safety, and convenience of administration of various GnRH-A. All GnRH-A (goserelin, triptorelin, buserelin, histrelin, and leuprorelin) have comparable potential to suppress testosterone (T) levels (≤50 ng/dL in a month and ≤20 ng/dL in 3 months). However, goserelin has shown better efficacy in maintaining T levels ≤50 ng/dL compared with leuprolide. The incidences of T escape are lower with goserelin and leuprolide than buserelin. Goserelin also has maximum benefit in prostate-specific antigen suppression. In neoadjuvant setting, when only goserelin was used, the 10-year overall survival (OS) rate was 42.6% to 86%. When either goserelin or leuprolide was used, the 10-year OS rate was 62%. As an adjuvant to radical prostatectomy, goserelin had a 10-year survival rate of 87%, and triptorelin had an 8-year survival rate of 84.6%. Goserelin further showed an absolute survival rate of 49% when used as an adjuvant to radiotherapy. The survival rates further improved when GnRH-A are used as combined androgen blockade compared with monotherapy. The frequency and severity of adverse events (hot flushes, fatigue, sexual dysfunction) are comparable among the GnRH-A. Goserelin appears to be the most convenient of all the GnRH-A for administration. Lack of conclusive comparative evidence makes it imperative to have a holistic approach of considering the patient profile and the disease characteristics to select the appropriate GnRH-A for ADT in prostate cancer.
Topics: Androgen Antagonists; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Prostatic Neoplasms
PubMed: 35343198
DOI: 10.4103/ijc.IJC_65_21 -
British Journal of Pharmacology Sep 2022Glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptor dual agonist have promising therapeutic effects in the treatment of obesity and diabetes. Moreover, GLP-1 and...
BACKGROUND AND PURPOSE
Glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptor dual agonist have promising therapeutic effects in the treatment of obesity and diabetes. Moreover, GLP-1 and cholecystokinin 2 (CCK ) dual agonists have been shown to restore pancreas function and improve glycaemic control in preclinical studies. We describe, for the first time, the beneficial effects of GLP-1/glucagon receptor and GLP-1/CCK dual agonists, which can be integrated into one peptide, resulting in significant anti-diabetes and anti-obesity effectiveness.
EXPERIMENTAL APPROACH
The in vitro potency of this novel peptide Xenopus (x) GLP-1/GCG/CCK tri-agonist (xGLP/GCG/gastrin) against GLP-1, GCG, CCK and CCK receptors was determined on cells expressing the corresponding receptors by cAMP accumulation or ERK1/2 phosphorylation assays. The in vivo anti-diabetes and anti-obesity effects of this tri-agonist xGLP/GCG/gastrin were studied in both db/db and diet induced obesity (DIO) mice.
KEY RESULTS
xGLP/GCG/gastrin was a potent and selective GLP-1, GCG and CCK tri-agonist. In DIO mice, the metabolic benefits of xGLP-1/GCG/gastrin, such as reduction of body weight and hepatic lipid contents were significantly better than those of the peptide ZP3022 (GLP-1/CCK-2 dual agonist) and liraglutide. In a short-term study in db/db mice, xGLP/GCG/gastrin treatment had considerable effects, increasing islet numbers, islet areas and insulin content. In a long-term treatment study using db/db mice, xGLP-1/GCG/gastrin showed a significantly and sustained improvement in glucose tolerance and glucose control compared with that of liraglutide, ZP3022, cotadutide (GLP-1/GCG dual agonist) and xGLP/GCG-15.
CONCLUSIONS AND IMPLICATIONS
These results demonstrate the therapeutic potential of xGLP-1/GCG/gastrin for the treatment of obesity and diabetes.
Topics: Animals; Cholecystokinin; Diabetes Mellitus; Gastrins; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Liraglutide; Mice; Obesity; Peptides; Receptors, Glucagon
PubMed: 35484823
DOI: 10.1111/bph.15860 -
Expert Opinion on Biological Therapy Dec 2021: CD40 signaling activates dendritic cells leading to improved T cell priming against tumor antigens. CD40 agonism expands the tumor-specific T cell repertoire and has... (Review)
Review
: CD40 signaling activates dendritic cells leading to improved T cell priming against tumor antigens. CD40 agonism expands the tumor-specific T cell repertoire and has the potential to increase the fraction of patients that respond to established immunotherapies.: This article reviews current as well as emerging CD40 agonist therapies with a focus on antibody-based therapies, including next generation bispecific CD40 agonists. The scientific rationale for different design criteria, binding epitopes, and formats are discussed.: The ability of CD40 agonists to activate dendritic cells and enhance antigen cross-presentation to CD8 T cells provides an opportunity to elevate response rates of cancer immunotherapies. While there are many challenges left to address, including optimal dose regimen, CD40 agonist profile, combination partners and indications, we are confident that CD40 agonists will play an important role in the challenging task of reprogramming the immune system to fight cancer.
Topics: Antibodies, Monoclonal; CD40 Antigens; CD8-Positive T-Lymphocytes; Dendritic Cells; Humans; Immunotherapy; Neoplasms
PubMed: 34043482
DOI: 10.1080/14712598.2021.1934446 -
Tijdschrift Voor Psychiatrie 2023Research suggests that cholinergic muscarinic 1 (M) and/or muscarinic 4 (M) receptors may be involved in the pathophysiology of psychotic disorders. Agonistic modulation... (Review)
Review
BACKGROUND
Research suggests that cholinergic muscarinic 1 (M) and/or muscarinic 4 (M) receptors may be involved in the pathophysiology of psychotic disorders. Agonistic modulation of these receptors can offer new treatment options.
AIM
To provide an overview of current research on the role of cholinergic M and M receptors in the development and treatment of psychoses, with special attention to the development of new drugs such as xanomeline and emraclidine.
METHOD
To obtain an overview, we searched for English-language studies published in PubMed, Embase, and PsycInfo up until June 1, 2023. We examined the role and effects of M and/or M agonists in schizophrenia. Additionally, we consulted clinical trial registers.
RESULTS
Our search strategy resulted in nine published articles on five clinical studies. These studies revealed that reduced presence of M receptors, primarily in the frontal cortex, and M receptors, primarily in the basal ganglia, are associated with psychoses. M and M receptors modulate dopaminergic activity in the ventral tegmentum and striatum through various pathways. Several M and/or M agonists, partial agonists, and positive allosteric modulators (PAMs) have been developed. Drugs exhibiting agonistic activity on M and/or M receptors, such as xanomeline-trospium (phase 2 and 3 studies) and emraclidine (phase 1b studies), have shown positive effects on cognitive and potentially negative symptoms in patients with schizophrenia.
CONCLUSION
M and/or M receptor agonists show potential as new treatment strategies for individuals with psychotic disorders. Although initial studies with xanomeline-trospium and emraclidine have shown positive results, further research is needed to assess their long-term efficacy, safety, and tolerability before these new medications can be evaluated.
Topics: Humans; Muscarinic Agonists; Psychotic Disorders; Receptor, Muscarinic M1; Receptor, Muscarinic M4
PubMed: 37947466
DOI: No ID Found -
Molecular Therapy. Nucleic Acids Mar 2024Activating cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) holds great potential for cancer immunotherapy by eliciting type-I interferon (IFN-I)...
Activating cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) holds great potential for cancer immunotherapy by eliciting type-I interferon (IFN-I) responses. Yet, current approaches to cGAS-STING activation rely on STING agonists, which suffer from difficult formulation, poor pharmacokinetics, and marginal clinical therapeutic efficacy. Here, we report nature-inspired oligonucleotide, Svg3, as a cGAS agonist for cGAS-STING activation in tumor combination immunotherapy. The hairpin-shaped Svg3 strongly binds to cGAS and enhances phase separation to form Svg3-cGAS liquid-like droplets. This results in cGAS-specific immunoactivation and robust IFN-I responses. Remarkably, Svg3 outperforms several state-of-the-art STING agonists in murine and human cells/tissues. Nanoparticle-delivered Svg3 reduces tumor immunosuppression and potentiates immune checkpoint blockade therapeutic efficacy of multiple syngeneic tumor models in wild-type mice, but in neither nor mice. Overall, these results demonstrate the great potential of Svg3 as a cGAS agonistic oligonucleotide for cancer combination immunotherapy.
PubMed: 38352859
DOI: 10.1016/j.omtn.2024.102126 -
RSC Medicinal Chemistry Jul 2021Several synthetic heterocyclic small molecules like imiquimod, resiquimod, CL097, CL075, bromopirone, tilorone, loxoribine and isatoribine demonstrated TLR7/8 agonistic... (Review)
Review
Several synthetic heterocyclic small molecules like imiquimod, resiquimod, CL097, CL075, bromopirone, tilorone, loxoribine and isatoribine demonstrated TLR7/8 agonistic activity and relatively modest structural changes in such molecules result in major variation in the TLR7 and/or TLR8 activity. A strict dependency of the electronic configuration of the heterocyclic system was also observed to influence the agonistic activity. In the present review, an evolution of imidazole based TLR7/8 agonist from imidazoquinoline based scaffold is delineated along with the elaboration of detailed structure activity relationship (SAR) in each chemotype. The structural and activity details of not only the active compounds but also the related inactive compounds are included to better understand the SAR. TLR7/8 agonists are emerging as promising vaccine adjuvant candidates and the present SAR and structural information will provide a road map towards the identification of more potent and appropriate candidates for further drug discovery.
PubMed: 34355178
DOI: 10.1039/d1md00031d -
Journal of Theoretical Biology Nov 2019This paper describes the behavior of binding and functional receptor systems where an antagonist of the receptor/G protein binding reaction is added as a blocker of...
This paper describes the behavior of binding and functional receptor systems where an antagonist of the receptor/G protein binding reaction is added as a blocker of agonist-induced receptor function. For agonist radioligands, the reduction of G protein receptor interaction leads to a possible change in the binding affinity of the agonist radioligand to the receptor. Reciprocally, the allosteric cooperativity between the agonist and the G protein binding site antagonist (quantified by the factor γ) affects the potency of the G protein antagonist modulator; this model presents the various profiles that would be expected for modulators that reduce (γ = 0.01), have no effect on (γ = 1) and increase (γ = 100) the affinity of the agonist for the receptor. It will be seen that modulators that increase the affinity of the receptor for the agonist are the most potent antagonists and may attain a profile of some special negative allosteric modulators referred to as PAM antagonists. In all cases, these modulators will be inverse agonists of constitutive receptor activity. This model presents a strategy for the discovery of PAM antagonists for therapeutic blockade of physiological signaling.
Topics: GTP-Binding Proteins; Ligands; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 31356763
DOI: 10.1016/j.jtbi.2019.07.014