Novel Agonist Bioisosteres and Common Structure-Activity Relationships for The Orphan G Protein-Coupled Receptor GPR139 (original) (raw)
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Bioorganic & Medicinal Chemistry Letters, 2011
We herein outline the design of a new series of agonists of the pancreatic and GI-expressed orphan G-protein coupled receptor GPR119, a target that has been of significant recent interest in the field of metabolism, starting from our prototypical agonist AR231453. A number of key parameters were improved first by incorporation of a pyrazolopyrimidine core to create a new structural series and secondly by the introduction of a piperidine ether group capped with a carbamate. Chronic treatment with one compound from the series, 3k, showed for the first time that blood glucose and glycated hemoglobin (HbA1c) levels could be significantly reduced in Zucker Diabetic Fatty (ZDF) rats over several weeks of dosing. As a result of these and other data described here, 3k (APD668, JNJ-28630368) was the first compound with this mechanism of action to be progressed into clinical development for the treatment of diabetes.
Identification of a Novel Small-Molecule Agonist for Human G Protein–Coupled Receptor 3
Journal of Pharmacology and Experimental Therapeutics, 2014
GPR3 is an orphan G protein-coupled receptor (GPCR) predominantly expressed in mammalian brain and oocytes. GPR3 plays important roles in these two organs and is known as a Gα s-coupled receptor activated constitutively in cells. However, the signal transduction pathway and pharmacological function of GPR3 remain unclear due to the lack of a specific ligand. Using a HEK293 cell line stably expressing flag-GPR3-GFP, a chemical screening for GPR3 ligands was performed using homogeneous time resolved fluorescence (HTRF) cAMP assay. Diphenyleneiodonium chloride (DPI) was identified as a novel agonist of GPR3 with weak or no cross-reactivity with other GPCRs. DPI was further characterized to activate several GPR3-mediated signal transduction pathways, including Ca 2+ mobilization, cAMP accumulation, membrane recruitment of β-arrestin2 and receptor desensitization. Parallel studies revealed that the activity of DPI is much more pronounced than S1P, a previously reported GPR3 agonist. Our study identified a novel and specific agonist of GPR3, which provides a useful tool for further study of this orphan GPCR.
2021
GPR85 is a member of the G protein-coupled receptor and is a super-conserved receptor expressed in the brain sub-family (SREB) with GPR27 and GPR173. These three receptors are “orphan receptors”; however, their endogenous ligands have not been identified. SREB has garnered the interest of many scientists because it is expressed in the central nervous system and is evolutionarily conserved. In particular, brain mass is reported to be increased and learning and memory are improved in GPR85 knockout mice (Matsumoto et al., 2008). In this study, we characterized newly synthesized compounds using a GPR85-Gsα fusion protein and the [35S]GTPγS binding assay and identified novel GPR85 inverse-agonists with IC50 values of approximately 1 µM. To analyze the neurochemical character of the compounds and investigate the physiological significance of GPR85, we used cerebellar Purkinje cells expressing GPR85 and an electrophysiological technique. Based on the results, the inverse-agonist compound ...
G protein-coupled receptors: structure- and function-based drug discovery
Signal Transduction and Targeted Therapy
As one of the most successful therapeutic target families, G protein-coupled receptors (GPCRs) have experienced a transformation from random ligand screening to knowledge-driven drug design. We are eye-witnessing tremendous progresses made recently in the understanding of their structure–function relationships that facilitated drug development at an unprecedented pace. This article intends to provide a comprehensive overview of this important field to a broader readership that shares some common interests in drug discovery.
Screening for Selective Ligands for GPR55 - Agonists
The orphan G protein coupled receptor, GPR55, has gained notoriety because of its putative identification as a cannabinoid receptor subtype. The significance of this assignment should not be underestimated given the importance of cannabinoids to drug abuse and the potential utility of cannabinoid ligands in treating behavioral disorders leading to conditions such as obesity. The validity of assigning GPR55 to the cannabinoid family is problematic based upon the discovery that endogenous compounds not related to cannabinoid receptor ligands also bind and signal through GPR55. As a consequence, it is important to identify GPR55-selective ligands that can precisely define GPR55’s role in regulating addictive behaviors. Lysophosphatidylinositol (LPI; 1.2 μM) is representative of the recently identified endogenous GPR55 ligands and the CB1 inverse agonist/antagonists SR141716A (3.9 μM) and AM251 (9.6 μM), that are also GPR55 agonists, are representative of the cannabinoid receptor ligand...
Journal of Medicinal Chemistry, 2012
26RFa, a novel RFamide neuropeptide, is the endogenous ligand of the former orphan receptor GPR103. Intracerebroventricular injection of 26RFa and its C-terminal heptapeptide, 26RFa (20−26) , stimulates food intake in rodents. To develop potent, stable ligands of GPR103 with low molecular weight, we have designed a series of aza-β 3 -containing 26RFa (20−26) analogues for their propensity to establish intramolecular hydrogen bonds, and we have evaluated their ability to increase [Ca 2+ ] i in GPR103-transfected cells. We have identified a compound, [Cmpi 21 ,aza-β 3 -Hht 23 ]26RFa (21−26) , which was 8-fold more potent than 26RFa (20−26) in mobilizing [Ca 2+ ] i . This pseudopeptide was more stable in serum than 26RFa (20−26) and exerted a longer lasting orexigenic effect in mice. This study constitutes an important step toward the development of 26RFa analogues that could prove useful for the treatment of feeding disorders.
Discovery of a Potent and Selective GPR120 Agonist
Journal of Medicinal Chemistry, 2012
GPR120 is a receptor of unsaturated long-chain fatty acids reported to mediate GLP-1 secretion, insulin sensitization, anti-inflammatory, and anti-obesity effects and is therefore emerging as a new potential target for treatment of type 2 diabetes and metabolic diseases. Further investigation is however hindered by the lack of suitable receptor modulators. Screening of FFA1 ligands provided a lead with moderate activity on GPR120 and moderate selectivity over FFA1. Optimization led to the discovery of the first potent and selective GPR120 agonist.