scholarly journals Discovery of a Novel Non-Narcotic Analgesic Derived from the CL-20 Explosive: Synthesis, Pharmacology, and Target Identification of Thiowurtzine, a Potent Inhibitor of the Opioid Receptors and the Ion Channels

ACS Omega ◽  
2021 ◽  
Author(s):  
Stephanie Aguero ◽  
Simon Megy ◽  
Valeria V. Eremina ◽  
Alexander I. Kalashnikov ◽  
Svetlana G. Krylova ◽  
...  
Keyword(s):  
Ion Channels ◽  
Opioid Receptors ◽  
Potent Inhibitor ◽  
Target Identification ◽  
Narcotic Analgesic ◽  
Explosive Synthesis

scholarly journals Discovery of a Novel Non-Narcotic Analgesic Derived from the CL-20 Explosive: Synthesis, Pharmacology and Target Identification of Thio-wurtzine, a Potent Inhibitor of the Opioid Receptors and the Voltage-Dependent Calcium Channels

2021 ◽  
Author(s):  
Stephanie Aguero ◽  
Simon Megy ◽  
Raphael Terreux ◽  
Mailys Fournier ◽  
Daria Kulagina ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Opioid Receptors ◽  
Mechanism Of Action ◽  
Pain Treatment ◽  
Target Identification ◽  
Animal Experiments ◽  
Complex Mechanism ◽  
Narcotic Analgesics ◽  
Voltage Dependent

The number of candidate molecules for new non-narcotic analgesics is extremely limited. Here we report the identification of thiowurtzine, a new potent analgesic molecule with promising application in chronic pain treatment. We describe the chemical synthesis of this unique compound derived from the hexaazaisowurtzitane (CL-20) explosive molecule. Then we use animal experiments to assess its analgesic activity in vivo upon chemical, thermal and mechanical exposures, compared to the effect of several reference drugs. Finally, we investigate the potential receptors of thiowurtzine in order to better understand its complex mechanism of action. We use docking, molecular modeling and molecular dynamics simula-tions to identify and characterize the potential targets of the drug and confirm the results of the animal experiments. Our findings finally indicate that thiowurtzine may have a complex mechanism of action, by targeting the mu, kappa, delta and ORL1 opioid receptors, and the voltage-gated calcium channels as well.

scholarly journals Scalaradial Is a Potent Inhibitor of Transient Receptor Potential Melastatin 2 (TRPM2) Ion Channels

2017 ◽  
Vol 80 (10) ◽  
pp. 2741-2750 ◽  
Author(s):  
John G. Starkus ◽  
Peter Poerzgen ◽  
Kristine Layugan ◽  
Kelly Galbraith Kawabata ◽  
Jun-Ichi Goto ◽  
...  
Keyword(s):  
Ion Channels ◽  
Transient Receptor Potential ◽  
Potent Inhibitor ◽  
Receptor Potential ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

scholarly journals The G protein-biased PZM21 and TRV130 act as partial agonists of μ-opioid receptors signaling to ion channel targets

2018 ◽  
Author(s):  
Yevgen Yudin ◽  
Tibor Rohacs
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
G Protein ◽  
Opioid Receptors ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Partial Agonists ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
Μ Opioid Receptors

Opioids exert many of their acute effects through modulating ion channels via Gβγ subunits. Some of their side effects are attributed to β-arrestin recruitment, and several biased agonists that do not activate this pathway have been developed recently. Here we tested the effects of TRV130, PZM21 and herkinorin, three G-protein biased agonists of μ-opioid receptors (μOR), on ion channel targets. Compared to the full μOR agonist DAMGO, all three biased agonists induced smaller activation of G protein-coupled inwardly rectifying potassium channels (GIRK2), and smaller inhibition of Transient Receptor Potential Melastatin (TRPM3) channels. Furthermore, co-application of TRV130 or PZM21, but not herkinorin reduced the effects of DAMGO on both ion channels. CaV2.2 was also inhibited less by PZM21 and TRV130 than by DAMGO. TRV130, PZM21 and herkinorin were also less effective than DAMGO in inducing dissociation of the Gαi /Gβγ complex. We conclude that TRV130, PZM21 are partial agonists of μOR.

scholarly journals Drug targets: ligand and voltage gated ion channels

2017 ◽  
Vol 6 (2) ◽  
pp. 235 ◽  
Author(s):  
Nilan T. Jacob
Keyword(s):  
Drug Discovery ◽  
Ion Channels ◽  
Drug Targets ◽  
Target Identification ◽  
Ion Flow ◽  
Voltage Gated ◽  
Initial Stage ◽  
Voltage Gated Ion Channels ◽  
Channel Architecture ◽  
Gated Ion Channels

The elucidation of a drug target is one of the earliest and most important steps in the drug discovery process. Ion channels encompassing both the ligand gated and voltage gated types are the second most common drug targets after G-Protein Coupled Receptors (GPCR). Ion channels are basically pore forming membrane proteins specialized for conductance of ions as per the concentration gradient. They are further broadly classified based on the energy (ATP) dependence into active ion channels/pumps and passive ion channels. Gating is the regulatory mechanism of these ion channels by which binding of a specific molecule or alteration in membrane potential induces conformational change in the channel architecture to result in ion flow or its inhibition. Thus, the study of ligand and voltage gated ion channels becomes an important tool for drug discovery especially during the initial stage of target identification. This review aims to describe the ligand and voltage gated ion channels along with discussion on its subfamilies, channel architecture and key pharmacological modulators.

scholarly journals Recent advances in pain management

2020 ◽  
Vol 10 (1) ◽  
pp. 133
Author(s):  
Priyadarsini Baskaran ◽  
Venkatraman Karthikeayan ◽  
Anusha Natarajan
Keyword(s):  
Ion Channels ◽  
Pain Management ◽  
Drug Development ◽  
Target Identification ◽  
Unmet Need ◽  
The Novel ◽  
Preclinical Models ◽  
Recent Advances ◽  
Clinical Pain ◽  
Novel Targets

Pain is one of the most common complaints for which patients approach physicians. In spite of this there is a huge unmet need for developing medications for pain that are safe and efficacious. Owing to the heterogeneity of clinical pain and complex pathophysiology, target identification for drug development is difficult. Preclinical models have also proven unreliable for the development of novel analgesics. Recent advances in understanding the physiology of nociception has enabled the development of novel analgesics including abuse deterrent opioids, drugs targeting several receptors, ion channels and enzymes. This review will attempt to cover the physiology of nociception focusing on the novel targets, the challenges in development of novel analgesics and give an overview of the recently developed drugs and those in the pipeline for the management of pain.

scholarly journals ATP signaling in the integrative neural center of Aplysia californica

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
János Györi ◽  
Andrea B. Kohn ◽  
Daria Y. Romanova ◽  
Leonid L. Moroz
Keyword(s):  
Ion Channels ◽  
Potent Inhibitor ◽  
Aplysia Californica ◽  
P2x Receptors ◽  
Signaling System ◽  
Early Cleavage ◽  
Purinergic Transmission ◽  
Cleavage Stages ◽  
And Function ◽  
Atp Signaling

AbstractATP and its ionotropic P2X receptors are components of the most ancient signaling system. However, little is known about the distribution and function of purinergic transmission in invertebrates. Here, we cloned, expressed, and pharmacologically characterized the P2X receptors in the sea slug Aplysia californica—a prominent neuroscience model. AcP2X receptors were successfully expressed in Xenopus oocytes and displayed activation by ATP with two-phased kinetics and Na+-dependence. Pharmacologically, they were different from other P2X receptors. The ATP analog, Bz-ATP, was a less effective agonist than ATP, and PPADS was a more potent inhibitor of the AcP2X receptors than the suramin. AcP2X were uniquely expressed within the cerebral F-cluster, the multifunctional integrative neurosecretory center. AcP2X receptors were also detected in the chemosensory structures and the early cleavage stages. Therefore, in molluscs, rapid ATP-dependent signaling can be implicated both in development and diverse homeostatic functions. Furthermore, this study illuminates novel cellular and systemic features of P2X-type ligand-gated ion channels for deciphering the evolution of neurotransmitters.

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