Journal ArticleDOI
Discovery of XEN907, a spirooxindole blocker of NaV1.7 for the treatment of pain.
Sultan Chowdhury,Mikhail Chafeev,Shifeng Liu,Jianyu Sun,Vandna Raina,Ray Chui,Wendy B. Young,Rainbow Kwan,Jianmin Fu,Cadieux Jean-Jacques +9 more
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TLDR
Starting from the oxindole 2a identified through a high-throughput screening campaign, a series of Na(V)1.7 blockers were developed, which demonstrated a 10-fold increase in target potency versus the original HTS hit and represents a promising structure for further optimization efforts.Citations
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The Na(V)1.7 sodium channel: from molecule to man.
Sulayman D. Dib-Hajj,Yang Yang,Yang Yang,Joel A. Black,Joel A. Black,Stephen G. Waxman,Stephen G. Waxman +6 more
TL;DR: Homology modelling based on crystal structures of ion channels suggests an atomic-level structural basis for the altered gating of mutant NaV1.7 that causes pain.
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Conus Venom Peptide Pharmacology
TL;DR: The discovery of new bioactives using proteomic/transcriptomic approaches combined with high-throughput platforms and better defining conopeptide structure-activity relationships using relevant membrane protein crystal structures are expected to grow the already significant impact conopePTides have had as both research probes and leads to new therapies.
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Recent advances in the synthesis of biologically active spirooxindoles
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Oxindole: A chemical prism carrying plethora of therapeutic benefits.
TL;DR: This review will provide insights for the synthetic as well as medicinal chemist for the designing and synthesis of novel oxindole derivatives with novel improved range of pharmacological implications.
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Facile one-pot synthesis of novel dispirooxindole-pyrrolidine derivatives and their antimicrobial and anticancer activity against A549 human lung adenocarcinoma cancer cell line.
TL;DR: Novel dispirooxindole-pyrrolidine derivatives have been synthesized through 1,3-dipolar cycloaddition of an azomethine ylide generated from isatin and sarcosine with the dipolarophile 3-(1H-indol-3-yl)-3-Oxo-2-(2-oxoindolin- 3-ylidene)propanenitrile, and also spiro compound of acenaphthene
References
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Journal ArticleDOI
International Union of Pharmacology. XLVIII. Nomenclature and Structure-Function Relationships of Voltage-Gated Calcium Channels
TL;DR: The molecular relationships and physiological functions of these calcium channel proteins are presented and comprehensive information on their molecular, genetic, physiological, and pharmacological properties is provided.
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An SCN9A channelopathy causes congenital inability to experience pain
James J. Cox,Frank Reimann,Adeline K Nicholas,Gemma K. Thornton,Emma Roberts,Kelly Springell,G. Karbani,Hussain Jafri,Jovaria Mannan,Yasmin Raashid,Lihadh Al-Gazali,Henan Hamamy,Enza Maria Valente,Shaun Gorman,Richard Aled Williams,Duncan McHale,John N. Wood,Fiona M. Gribble,C. Geoffrey Woods +18 more
TL;DR: The data suggest that SCN9A is an essential and non-redundant requirement for nociception in humans, and should stimulate the search for novel analgesics that selectively target this sodium channel subunit.
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Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia
Yong Yang,Y Wang,Shugang Li,Z Xu,H Li,L Ma,J Fan,D Bu,Bingya Liu,Z Fan,G Wu,J Jin,B Ding,X Zhu,Y Shen +14 more
TL;DR: The data suggest that mutations in SCN9A cause primary erythermalgia, encoding a voltage-gated sodium channel alpha subunit predominantly expressed in sensory and sympathetic neurones, may play an important role in nociception and vasomotor regulation.
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SCN9A Mutations in Paroxysmal Extreme Pain Disorder: Allelic Variants Underlie Distinct Channel Defects and Phenotypes
Caroline Fertleman,Mark D. Baker,K. Parker,Sarah Moffatt,F. V. Elmslie,Bjarke Abrahamsen,Johan Ostman,Norbert Klugbauer,John N. Wood,R. Mark Gardiner,M Rees +10 more
TL;DR: A genome-wide linkage search followed by mutational analysis of the candidate gene SCN9A, which encodes hNa(v)1.7, identified eight missense mutations in 11 families and 2 sporadic cases of PEPD mutants that revealed a reduction in fast inactivation, leading to persistent sodium current.
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Sodium Channels in Normal and Pathological Pain
TL;DR: The contribution of voltage-gated sodium channels to pain is reviewed, with Na(v)1.7 is of special interest because it has been linked to a spectrum of inherited human pain disorders and is upregulated along pain-signaling pathways after nervous system injuries.