Tricyclic Spirolactones as Modular TRPV1 Synthetic Agonists

ACS Chemical Neuroscience
Yelena MostinskiAvi Priel

Abstract

TRPV1 is a prominent signal integrator of the pain system, known to be activated by vanilloids, a family of endogenous and exogenous pain-evoking molecules, through the vanilloid-binding site (VBS). The extensive preclinical profiling of small molecule inhibitors provides intriguing evidence that TRPV1 inhibition can be a useful therapeutic approach. However, the dissimilarity of chemical species that activate TRPV1 creates a major obstacle to understanding the molecular mechanism of pain induction, which is viewed as a pivotal trait of the somatosensory system. Here, we establish the existence of a unique family of synthetic agonists that interface with TRPV1 through the VBS, containing none of the molecular domains previously believed to be required for this interaction. The overarching value obtained from our inquiry is the novel advancement of the existing TRPV1 activation model. These findings uncover new potential in the area of pain treatment, providing a novel synthetic platform.

References

Feb 21, 2002·Cell·Sven-Eric Jordt, David Julius
May 7, 2004·European Journal of Biochemistry·Mario Van Der Stelt, Vincenzo Di Marzo
Mar 25, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Joseph R GhilardiPatrick W Mantyh
Jun 23, 2005·Pflügers Archiv : European journal of physiology·Makoto Tominaga, Tomoko Tominaga
Jul 27, 2005·Trends in Pharmacological Sciences·Arpad Szallasi
Jan 2, 2007·Seminars in Cell & Developmental Biology·David C Immke, Narender R Gavva
Jan 16, 2007·Handbook of Experimental Pharmacology·C K Colton, M X Zhu
Apr 28, 2007·Nature Reviews. Drug Discovery·Arpad SzallasiSamer R Eid
Apr 9, 2008·Nature Neuroscience·Man-Kyo ChungMichael J Caterina
Feb 25, 2009·The Journal of Alternative and Complementary Medicine : Research on Paradigm, Practice, and Policy·Merlin Willcox
Oct 20, 2009·Cell·Allan I BasbaumDavid Julius
Jul 1, 2010·Expert Opinion on Therapeutic Patents·Eric A Voight, Michael E Kort
Jul 12, 2012·Expert Opinion on Investigational Drugs·Arpad Szallasi, Mohamed Sheta
Jun 8, 2013·Journal of Natural Products·Sergio M BorghiWaldiceu A Verri
Oct 9, 2013·Annual Review of Cell and Developmental Biology·David Julius
Jul 22, 2015·Scientific Reports·Adina HazanAvi Priel
Oct 27, 2015·Molecular Pharmaceutics·Leonardo Darré, Carmen Domene
May 5, 2016·The Journal of Biological Chemistry·Rakesh KumarAvi Priel
Aug 27, 2016·Pharmaceuticals·Vincenzo Carnevale, Tibor Rohacs

❮ Previous
Next ❯

Citations

Nov 10, 2020·Drugs·Mircea IftincaChristophe Altier

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

Related Papers

Clinical and Experimental Pharmacology & Physiology
J W FunderI S Edelman
Polskie Archiwum Medycyny Wewnętrznej
M FALENCIK-EDELWEJN
© 2022 Meta ULC. All rights reserved