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Journal of Medicinal Chemistry Oct 2023The GPR139 receptor is an orphan G-protein-coupled receptor (GPCR) mainly found in the central nervous system and is a potential therapeutic target for the treatment of...
The GPR139 receptor is an orphan G-protein-coupled receptor (GPCR) mainly found in the central nervous system and is a potential therapeutic target for the treatment of schizophrenia and drug addiction. Guided by the reported structure of GPR139, we conducted medicinal chemistry optimizations of TAK-041, the GPR139 agonist in clinical trials. New compounds with three different core structures were designed and synthesized, and their activity at GPR139 was evaluated. Among them, compounds (EC = 31.4 nM) and (EC = 24.7 nM) showed potent agonist activity at GPR139 and good pharmacokinetic properties. In murine schizophrenia models, both compounds rescued the social interaction deficits observed in BALB/c mice. Compound also alleviated cognitive deficits in mice with a pharmacologically induced model of schizophrenia. These findings further demonstrated the potential of GPR139 agonists in alleviating the negative symptoms and cognitive deficits of schizophrenia. Compound is worth further evaluation as an antischizophrenia drug candidate.
Topics: Mice; Animals; Social Interaction; Receptors, G-Protein-Coupled; Triazines; Cognitive Dysfunction
PubMed: 37830160
DOI: 10.1021/acs.jmedchem.3c01034 -
European Journal of Medicinal Chemistry Feb 2024Cannabinoid CBR agonists have gained considerable attention as potential novel therapies for psychiatric disorders due to their non-psychoactive nature, in contrast to...
Cannabinoid CBR agonists have gained considerable attention as potential novel therapies for psychiatric disorders due to their non-psychoactive nature, in contrast to CBR agonists. In this study, we employed molecular docking to design and synthesize 23 derivatives of cannabidiol (CBD) with the aim of discovering potent CBR agonists rather than CBR antagonists or inverse agonists. Structure-activity relationship (SAR) investigations highlighted the critical importance of the amide group at the C-3' site and the cycloalkyl group at the C-4' site for CBR activation. Interestingly, three CBD derivatives, namely 2o, 6g, and 6h, exhibited substantial partial agonistic activity towards the CB receptor, in contrast to the inverse agonistic property of CBD. Among these, 2o acted as a CBR and 5-HTR dual agonist, albeit with some undesired antagonist activity for CBR. It demonstrated significant CBR partial agonism while maintaining a level of 5-HTR agonistic and CBR antagonistic activity similar to CBD. Pharmacokinetic experiments confirmed that 2o possesses favorable pharmacokinetic properties. Behavioral studies further revealed that 2o elicits significant antidepressant-like and anxiolytic-like effects while maintaining a good safety profile.
Topics: Humans; Receptor, Serotonin, 5-HT1A; Molecular Docking Simulation; Serotonin; Depression; Drug Inverse Agonism; Cannabinoid Receptor Agonists; Cannabidiol; Serotonin Receptor Agonists; Anxiety; Receptor, Cannabinoid, CB2; Receptor, Cannabinoid, CB1
PubMed: 38150961
DOI: 10.1016/j.ejmech.2023.116048 -
Journal of Medicinal Chemistry Apr 2023Orexins are a family of neuropeptides that regulate various physiological events, such as sleep/wakefulness as well as emotional and feeding behavior, and that act on...
Orexins are a family of neuropeptides that regulate various physiological events, such as sleep/wakefulness as well as emotional and feeding behavior, and that act on two G-protein-coupled receptors, i.e., orexin 1 (OXR) and orexin 2 receptors (OXR). Since the discovery that dysfunction of the orexin/OXR system causes the sleep disorder narcolepsy, several OXR-selective and OXR dual agonists have been disclosed. However, an OXR-selective agonist has not yet been reported, despite the importance of the biological function of OXR. Herein, we report the discovery of a potent OXR-selective agonist, (,)-3-(4-methoxy-3-(-(8-(2-(3-methoxyphenyl)--methylacetamido)-5,6,7,8-tetrahydronaphthalen-2-yl)sulfamoyl)phenyl)--(pyridin-4-yl)acrylamide [()-YNT-3708; EC = 7.48 nM for OXR; OXR/OXR EC ratio = 22.5]. The OXR-selective agonist ()-YNT-3708 exhibited antinociceptive and reinforcing effects through the activation of OXR in mice.
Topics: Mice; Animals; Orexins; Orexin Receptors; Receptors, G-Protein-Coupled; Neuropeptides; Sleep
PubMed: 37043436
DOI: 10.1021/acs.jmedchem.2c01773 -
Biophysical Journal May 2021Agonists are evaluated by a concentration-response curve (CRC), with a midpoint (EC) that indicates potency, a high-concentration asymptote that indicates efficacy, and...
Agonists are evaluated by a concentration-response curve (CRC), with a midpoint (EC) that indicates potency, a high-concentration asymptote that indicates efficacy, and a low-concentration asymptote that indicates constitutive activity. A third agonist attribute, efficiency (η), is the fraction of binding energy that is applied to the conformational change that activates the receptor. We show that η can be calculated from EC and the asymptotes of a CRC derived from either single-channel or whole-cell responses. For 20 agonists of skeletal muscle nicotinic receptors, the distribution of η-values is bimodal with population means at 51% (including acetylcholine, nornicotine, and dimethylphenylpiperazinium) and 40% (including epibatidine, varenicline, and cytisine). The value of η is related inversely to the size of the agonist's headgroup, with high- versus low-efficiency ligands having an average volume of 70 vs. 102 Å. Most binding site mutations have only a small effect on acetylcholine efficiency, except for αY190A (35%), αW149A (60%), and those at αG153 (42%). If η is known, the EC and high-concentration asymptote can be calculated from each other. Hence, an entire CRC can be estimated from the response to a single agonist concentration, and efficacy can be estimated from EC of a CRC that has been normalized to 1. Given η, the level of constitutive activity can be estimated from a single CRC.
Topics: Binding Sites; Nicotinic Agonists; Receptors, Nicotinic
PubMed: 33675765
DOI: 10.1016/j.bpj.2021.02.034 -
Journal of Controlled Release :... May 2023Stimulator of interferon genes (STING) pathway is the key innate immune pathway involving in cancer immunity. Emerging new molecules and drug delivery systems have made...
Stimulator of interferon genes (STING) pathway is the key innate immune pathway involving in cancer immunity. Emerging new molecules and drug delivery systems have made systemic STING agonist immunotherapy possible and demonstrated efficient tumor eradication in preclinical studies. In this perspective, we will discuss the potential mechanisms of STING agonism as a multifaceted anti-cancer therapy and the pharmacological challenges associated with systemic delivery of STING agonists on the level of organs, tissues, cells, and intracellular compartments. We will present and discuss drug delivery strategies to address these challenges. New advances in the field can unlock the promise of systemic STING agonist as effective and safe cancer immunotherapy.
Topics: Humans; Immunotherapy; Membrane Proteins; Neoplasms; Signal Transduction
PubMed: 37001564
DOI: 10.1016/j.jconrel.2023.03.047 -
Neoplasma Mar 2022Numerous studies have confirmed the anticancer effects of ferroptosis on a wide range of tumors, specifically in providing new perspectives for tackling drug resistance...
Numerous studies have confirmed the anticancer effects of ferroptosis on a wide range of tumors, specifically in providing new perspectives for tackling drug resistance and treating refractory tumors. Notably, mechanisms of improving tumor susceptibility to ferroptosis have been a focus of current research. This study discovered that co-treatment of LXRS agonist T0901317 and ferroptosis inducers (FINs) significantly inhibited the proliferation of cancer cells, this inhibition effect could be reversed by specific inhibitors of ferroptosis and accompanied by elevated lipid peroxides. Glutathione peroxidase 4 (GPX4) regulates T0901317 induced ferroptotic sensitization, and its overexpression dramatically reverses the joint anticancer effect of T0901317 and FINs. Furthermore, xenograft model results highly confirmed the ferroptotic sensitization effect of T0901317 in vivo. In summary, our findings indicate that drug combination and ferroptosis induction strategies provide novel options for cancer therapy.
Topics: Animals; Cell Line, Tumor; Ferroptosis; Fluorocarbons; Humans; Liver X Receptors; Neoplasms; Sulfonamides; Xenograft Model Antitumor Assays
PubMed: 35081722
DOI: 10.4149/neo_2021_210810N1132 -
Anesthesia and Analgesia Feb 2023Increasing attention has been attracted to the development of bifunctional compounds to minimize the side effects of opioid analgesics. Pharmacological studies have...
BACKGROUND
Increasing attention has been attracted to the development of bifunctional compounds to minimize the side effects of opioid analgesics. Pharmacological studies have verified the functional interaction between opioid and cannabinoid systems in pain management, suggesting that coactivation of the opioid and cannabinoid receptors may provide synergistic analgesia with fewer adverse reactions. Herein, we developed and characterized a novel bifunctional compound containing the pharmacophores of the mu-opioid receptor agonist DALDA and the cannabinoid peptide VD-Hpα-NH2, named OCP002.
METHODS
The opioid and cannabinoid agonistic activities of OCP002 were investigated in calcium mobilization and western blotting assays, respectively. Moreover, the central and peripheral antinociceptive effects of OCP002 were evaluated in mouse preclinical models of tail-flick test, carrageenan-induced inflammatory pain, and acetic acid-induced visceral pain, respectively. Furthermore, the potential opioid and cannabinoid side effects of OCP002 were systematically investigated in mice after intracerebroventricular (ICV) and subcutaneous (SC) administrations.
RESULTS
OCP002 functioned as a mixed agonist toward mu-opioid, kappa-opioid, and cannabinoid CB1 receptors in vitro. ICV and SC injections of OCP002 produced dose-dependent antinociception in mouse models of nociceptive (the median effective dose [ED50] values with 95% confidence interval [CI] are 0.14 [0.12-0.15] nmol and 0.32 [0.29-0.35] μmol/kg for ICV and SC injections, respectively), inflammatory (mechanical stimulation: ED50 values [95% CI] are 0.76 [0.64-0.90] nmol and 1.23 [1.10-1.38] μmol/kg for ICV and SC injections, respectively; thermal stimulation: ED50 values [95% CI] are 0.13 [0.10-0.17] nmol and 0.23 [0.08-0.40] μmol/kg for ICV and SC injections, respectively), and visceral pain (ED50 values [95% CI] are 0.0069 [0.0050-0.0092] nmol and 1.47 [1.13-1.86] μmol/kg for ICV and SC injections, respectively) via opioid and cannabinoid receptors. Encouragingly, OCP002 cannot cross the blood-brain barrier and exerted nontolerance-forming analgesia over 6-day treatment at both supraspinal and peripheral levels. Consistent with these behavioral results, repeated OCP002 administration did not elicit microglial hypertrophy and proliferation, the typical features of opioid-induced tolerance, in the spinal cord. Furthermore, at the effective analgesic doses, SC OCP002 exhibited minimized opioid and cannabinoid side effects on motor performance, body temperature, gastric motility, physical and psychological dependence, as well as sedation in mice.
CONCLUSIONS
This study demonstrates that OCP002 produces potent and nontolerance-forming antinociception in mice with reduced opioid- and cannabinoid-related side effects, which strengthen the candidacy of bifunctional drugs targeting opioid/cannabinoid receptors for translational-medical development to replace or assist the traditional opioid analgesics.
Topics: Animals; Mice; Analgesics; Analgesics, Opioid; Cannabinoids; Dose-Response Relationship, Drug; Receptors, Cannabinoid; Receptors, Opioid; Visceral Pain; Cannabinoid Receptor Agonists
PubMed: 36638515
DOI: 10.1213/ANE.0000000000006266 -
Journal of Medicinal Chemistry Jan 2021Toll-like receptors (TLRs) are the pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) in microbial species. Among the... (Review)
Review
Toll-like receptors (TLRs) are the pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) in microbial species. Among the various TLRs, TLR2 has a special place due to its ability to sense the widest repertoire of PAMPs owing to its heterodimerization with either TLR1 or TLR6, broadening its ligand diversity against pathogens. Various scaffolds are reported to activate TLR2, which include naturally occurring lipoproteins, synthetic lipopeptides, and small heterocyclic molecules. We described a detailed SAR in TLR2 agonistic scaffolds and also covered the design and chemistry for the conjugation of TLR2 agonists to antigens, carbohydrates, polymers, and fluorophores. The approaches involved in delivery of TLR2 agonists such as lipidation of antigen, conjugation to polymers, phosphonic acids, and other linkers to achieve surface adsorption, liposomal formulation, and encapsulating nanoparticles are elaborated. The crystal structure analysis and computational modeling are also included with the structural features that facilitate TLR2 activation.
Topics: Animals; Crystallography, X-Ray; Humans; Molecular Structure; Small Molecule Libraries; Structure-Activity Relationship; Toll-Like Receptor 2
PubMed: 33346636
DOI: 10.1021/acs.jmedchem.0c01627 -
European Journal of Medicinal Chemistry Feb 2023RORγt plays an important role in mediating IL-17 production and some tumor cells. It has four functional domains, of which the ligand-binding domain (LBD) is... (Review)
Review
RORγt plays an important role in mediating IL-17 production and some tumor cells. It has four functional domains, of which the ligand-binding domain (LBD) is responsible for binding agonists to recruit co-activators or inverse agonists to prevent co-activator recruiting the agonists. Thus, potent ligands targeting the LBD of this protein could provide novel treatments for cancer and autoimmune diseases. In this perspective, we summarized and discussed various modes of action (MOA) of RORγt-ligand binding structures. The ligands can bind with RORγt at either orthosteric site or the allosteric site, and the binding modes at these two sites are different for agonists and inverse agonist. At the orthosteric site, the binding of agonist is to stabilize the H479-Y502-F506 triplet interaction network of RORγt. The binding of inverse agonist features as these four apparent ways: (1) blocking the entrance of the agonist pocket in RORγt; (2) directly breaking the H479-Y502 pair interactions; (3) destabilizing the triplet H479-Y502-F506 interaction network through perturbing the conformation of the side chain in M358 at the bottom of the binding pocket; (4) and destabilizing the triplet H479-Y502-F506 through changing the conformation of the side chain of residue W317 side chain. At the allosteric site of RORγt, the binding of inverse agonist was found recently to inhibit the activation of protein by interacting directly with H12, which results in unfolding of helix 11' and orientation of H12 to directly block cofactor peptide binding. This overview of recent advances in the RORγt structures is expected to provide a guidance of designing more potent drugs to treat RORγt-related diseases.
Topics: Nuclear Receptor Subfamily 1, Group F, Member 3; Ligands; Drug Inverse Agonism; Receptors, Retinoic Acid; Protein Binding
PubMed: 36566711
DOI: 10.1016/j.ejmech.2022.115039 -
Research and Practice in Thrombosis and... Feb 2023A state-of-the-art lecture titled "Preeclampsia and Platelet Procoagulant Membrane Dynamics" was presented at the International Society on Thrombosis and Haemostasis...
A state-of-the-art lecture titled "Preeclampsia and Platelet Procoagulant Membrane Dynamics" was presented at the International Society on Thrombosis and Haemostasis (ISTH) Congress in 2022. Platelet activation is involved in the pathophysiology of preeclampsia and contributes to the prothrombotic state of the disorder. Still, it remains unclear what mechanisms initiate and sustain platelet activation in preeclampsia and how platelets drive the thrombo-hemorrhagic abnormalities in preeclampsia. Here, we highlight our findings that platelets in preeclampsia are preactivated possibly by plasma procoagulant agonist(s) and overexpress facilitative glucose transporter-3 (GLUT3) in addition to GLUT1. Preeclampsia platelets are also partially degranulated, procoagulant, and proaggregatory and can circulate as microaggregates/microthrombi. However, in response to exposed subendothelial collagen, such as in injured vessels during cesarean sections, preeclampsia platelets are unable to mount a full procoagulant response, contributing to blood loss perioperatively. The overexpression of GLUT3 or GLUT1 may be monitored alone or in combination (GLUT1/GLUT3 ratio) as a biomarker for preeclampsia onset, phenotype, and progression. Studies to further understand the mediators of the platelet activation and procoagulant membrane dynamics in preeclampsia can reveal novel drug targets and suitable alternatives to aspirin for the management of prothrombotic tendencies in preeclampsia. Finally, we summarize relevant new data on this topic presented during the 2022 ISTH Congress.
PubMed: 36923708
DOI: 10.1016/j.rpth.2023.100075