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Chemical Structure| 14199-15-6 Chemical Structure| 14199-15-6
Chemical Structure| 14199-15-6

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Zhuang, Youwen ; Wang, Kai ; Dimova, Snezana T ; Hanson, John N ; Thakur, Abhishek ; Xu, Youwei , et al.

Abstract: Allosteric modulation of G protein-coupled receptors (GPCRs) is an emerging therapeutic paradigm that has proven effective, yet the cooperative action of multiple modulators remains unexplored. Here, we reveal how positive allosteric modulators (PAMs) synergistically enable extraordinary signal amplification through the D1 dopamine receptor (D1R). We developed UNC9815 and UNC10062 as enhanced D1R PAMs from the parent compound MLS6585, and then employed cryo-electron microscopy to reveal concurrent occupancy of three distinct allosteric sites by PAMs of different scaffolds, including LY3154207, BMS-A1, and our UNC compounds. Remarkably, we discovered two adjacent allosteric pockets at the transmembrane helix (TM) 1-7 interface: BMS-A1 occupies an intracellular site promoting activation through TM7 conformational shifts, while the UNC compounds complementarily stabilize the extracellular side of the interface. When combined with LY3154207, this cooperative architecture enhances dopamine potency by more than 1,000-fold. These findings elucidate the first structural blueprint for multi-site GPCR cooperativity, unlocking transformative therapeutic strategies inaccessible to orthosteric and single- site allosteric drugs.

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Fischer, Thomas ; Frasson, David ; Sievers, Martin ; Riedl, Rainer ;

Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) papain-like cysteine protease (PLpro) represents one of only two essential cysteine proteases involved in the regulation of viral replication. It, therefore, qualifies as a promising therapeutic target for the development of antiviral agents. We identified a previously synthesized protease inhibitor, resulting from an earlier project, as a PLpro inhibitor and crafted a structure-activity relationship around the hit, leading to the more potent inhibitors ZHAWOC6941 (17h) and ZHAWOC25153 (17o) displaying IC50 values of 8 and 7 µM, respectively. The two compounds represent a new class of PLpro inhibitors and, with single‐digit micromolar IC50 values, are comparable to inhibitors found in the literature.

Keywords: Inhibitor ; papain-like protease ; SARS-CoV-2 ; structure-activity relationship

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Alternative Products

Product Details of Methyl 4-hydroxyphenylacetate

CAS No. :14199-15-6
Formula : C9H10O3
M.W : 166.17
SMILES Code : C1=C(CC(OC)=O)C=CC(=C1)O
MDL No. :MFCD00002387
InChI Key :XGDZEDRBLVIUMX-UHFFFAOYSA-N
Pubchem ID :518900

Safety of Methyl 4-hydroxyphenylacetate

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Application In Synthesis of Methyl 4-hydroxyphenylacetate

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 14199-15-6 ]
  • Downstream synthetic route of [ 14199-15-6 ]

[ 14199-15-6 ] Synthesis Path-Upstream   1~1

  • 1
  • [ 14199-15-6 ]
  • [ 10338-51-9 ]
References: [1] Chemical and Pharmaceutical Bulletin, 1998, vol. 46, # 4, p. 581 - 586.
 

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