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Class a gpcr-binding compound modifier

A compound and binding technology, applied in the direction of DNA / RNA fragments, antibodies, sugar derivatives, etc., can solve problems that are not suitable for G protein coupling or agonist binding

Pending Publication Date: 2020-03-06
RIKEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In other words, the GPCR structure stabilized in the inactive state is efficient for antagonist binding but not suitable for G protein coupling or agonist binding due to the sodium ion-centered water molecule cluster.

Method used

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  • Class a gpcr-binding compound modifier

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0165] 1.1 Expression of BLT1 variants for the purpose of BLT1 characterization

[0166] For evaluation by the consistency method ( Figure 8 A) Thermostability of designed guinea pig BLT1 variants, using QuikChange kit (Agilent) to thermally stabilized BLT1 variant cDNA previously constructed in pcDNA3 vector (removal of residues 1-14, with H83G / K88G / S309A mutations and N-terminal with FLAG tag) introduced point mutation (Hori, T. et al., Protein Expr. Purif. 72 (2010) 66-74, Hori, T. et al., Biochem. Biophys. Rep. 4 (2015) 243-249). COS-7 cells were transfected with expression vectors encoding BLT1 variants using Lipofectamine2000. To analyze the BIIL260-binding residue of BLT1, the cDNA introduction point of wild-type BLT1 with a FLAG tag at the N-terminus in the pcDNA3 vector was mutated using In-Fusion enzyme (Clontech). Expression vectors were transfected into HEK293 cells using polyethyleneimine. For the benzamidine competition assay, HEK293 cells were transfected w...

Embodiment 2

[0240] 2.1 Functional analysis of compounds having a structure in which class A GPCR-binding compounds bind to benzamidine groups

[0241] 2.1.1 Synthesis of compounds

[0242] A compound (compound 1) having a structure in which a benzamidine group is bound to carbazole (adrenoceptor ligand), and a structure in which a benzamidine group is bound to adenosine (A 2A Adenosine receptor ligand) compound (compound 2), and histamine (compound 3, 4) compounds having a structure in which a benzamidine group is bound to histamine (histamine receptor ligand). Proceed as follows. It should be noted that the following compounds 43-28 correspond to compound 4, compounds 42-28 correspond to compound 3, compounds 7-28 correspond to compound 2, and compounds 15-28 correspond to compound 1.

[0243] 2.1.1.1 Synthesis of compounds 43-28, 42-28

[0244]

[0245] Nitrobenzenesulfonylation of histamine dihydrochloride and Mitsunobu reaction followed by click reaction synthesis with an additi...

Embodiment 3

[0310] 3.1 Functional analysis of benzamidine derivatives

[0311] 3.1.1 Compounds

[0312] Compound 0 (benzamidine hydrochloride hydrate) and compounds 1, 3-5, 7, 11-13 (benzamidine derivatives) listed in Table 4 were purchased. Compound 14 (benzamidine derivative) used the above S1. The structure of the protonation state of each compound is shown in Figure 19 .

[0313] 【Table 4】

[0314] serial number Compound name seller Catalog number 0 Benzamidine Hydrochloride Hydrate sigma-aldrich corp. B6506-5G 1 1H-pyrazole-1-carboxamidine hydrochloride sigma-aldrich corp. 402516-10G 3 Pyrrolidine-1-carboxamidine hydroiodide sigma-aldrich corp. CDS014943-100MG 4 benzamide oxime sigma-aldrich corp. CDS001188-50MG 5 Piperidine-1-carboxamide hydrobromic acid sigma-aldrich corp. CDS014887-100MG 7 Cyclopropanecarboxamide hydrochloride Tokyo chemical C2344 11 1-(o-tolyl)biguanide Tokyo chemical T0314 ...

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Abstract

Provided are a novel class A GPCR antagonist, a production method for same, and a novel compound which interacts with the binding site of a class A GPCR Na+- water molecule cluster. A compound, or a salt thereof, having a structure in which are bonded a class A GPCR-binding compound and a functional group that binds to a class A GPCR Na+- water molecule cluster binding site. A class A GPCR antagonist production method comprises a step for binding, to another compound, a compound that binds to a class A GPCR Na+- water molecule cluster binding site.

Description

technical field [0001] The present invention relates to class A GPCR antagonists or methods of designing or making class A GPCR antagonists. 【Background technique】 [0002] The three-dimensional structure of class A (known as the rhodopsin family) G protein-coupled receptors (GPCRs) is determined by extracellular and intracellular molecules (eg, agonists, inverse agonists, mutants). regulatory factors, G proteins, lipids, and sodium ions) regulation (non-patent literature 1, 2). For example, the coupling of the G protein to the GPCR shifts the equilibrium of the GPCR's stereostructure to a high-affinity agonist-bound state compared to the receptor in the uncoupled state. The allosteric ligand binds to a site other than the orthosteric binding site of the GPCR, modulating the binding affinity or signal transduction efficiency of the orthosteric agonist to the GPCR line either positively or negatively. Sodium ions also act as transgenic regulators of GPCR activity. [0003]...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12A61K31/4192A61K31/7076A61K39/395A61K45/00A61P43/00C07H19/167C07K16/40
CPCC07D403/12C07H19/167C07K16/28C12N15/115C07C279/26C07C211/34C07C233/64C07C211/33C07C257/18C07C259/18C07C233/57C07C211/39C07C259/16C07C257/16C07C279/18C07C211/44C07C279/16
Inventor 横山茂之堀哲哉
Owner RIKEN