Synthesis of β<sub>2</sub>-AR Agonist BI-167107

王江波,; Ahn, Seungkirl; Kahsai, Alem W.; 刘蓉,; 任杰,; 胡昆,; 孙小强,; 陈新,

doi:10.6023/cjoc201211015

Cited by 4 publications

(5 citation statements)

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“…We maintained the purified receptor in maltose–neopentyl glycol (MNG) 35 , an amphiphilic detergent that enhances receptor stability. In order to lock the receptor into an active conformation for selection of RNA aptamers, an agonist of high affinity and extremely slow off-rate, BI167107 12 , 36 , was used ( Fig. 1a ).…”

Section: Resultsmentioning

confidence: 99%

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Conformationally selective RNA aptamers allosterically modulate the β2-adrenoceptor

et al. 2016

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G-protein-coupled receptor (GPCR) ligands function by stabilizing multiple, functionally distinct receptor conformations. This property underlies how “biased agonists” activate specific subsets of a given receptor’s signaling profile. However, stabilization of distinct active GPCR conformations to enable structural characterization of mechanisms underlying GPCR activation remains difficult. These challenges have accentuated the need for receptor tools that allosterically stabilize and regulate receptor function via unique, previously unappreciated mechanisms. Here, utilizing a highly diverse RNA library combined with advanced selection strategies involving state-of-the-art next-generation sequencing and bioinformatics analyses, we identify RNA aptamers that bind a prototypical GPCR, β2-adrenoceptor (β2AR). Using biochemical, pharmacological, and biophysical approaches, we demonstrate that these aptamers bind with nanomolar affinity at defined surfaces of the receptor, allosterically stabilizing active, inactive, and ligand-specific receptor conformations. The discovery of RNA aptamers as allosteric GPCR modulators significantly expands the diversity of ligands available to study the structural and functional regulation of GPCRs.

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Section: Resultsmentioning

confidence: 99%

“…Sf9 cell culture media and transfection kits to generate virus stocks were purchased from Expression Systems. BI-167107 36 , synthesized as described previously 36 , was a generous gift from Dr. Xin Chen (Changzhou University, Changzhou, Jiangsu, China). All other ligands were purchased from Sigma-Aldrich.…”

Section: Methodsmentioning

confidence: 99%

Conformationally selective RNA aptamers allosterically modulate the β2-adrenoceptor

et al. 2016

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“…Cmpd-6 and its analogs were synthesized using the methods described below. With the exception of BI-167107, which was synthesized as described previously ( Wang et al, 2013 ), all of the orthosteric β 2 AR ligands used were purchased from Sigma-Aldrich (St. Louis, MO) and sourced at a 95% or greater purity. Nuevolution provided the DNA-encoded libraries used for screening.…”

Section: Methodsmentioning

confidence: 99%

Small-Molecule Positive Allosteric Modulators of the β2-Adrenoceptor Isolated from DNA-Encoded Libraries

Ahn

Pani

Kahsai

et al. 2018

Molecular Pharmacology

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Conventional drug discovery efforts at the β2-adrenoceptor (β2AR) have led to the development of ligands that bind almost exclusively to the receptor’s hormone-binding orthosteric site. However, targeting the largely unexplored and evolutionarily unique allosteric sites has potential for developing more specific drugs with fewer side effects than orthosteric ligands. Using our recently developed approach for screening G protein–coupled receptors (GPCRs) with DNA-encoded small-molecule libraries, we have discovered and characterized the first β2AR small-molecule positive allosteric modulators (PAMs)—compound (Cmpd)-6 [(R)-N-(4-amino-1-(4-(tert-butyl)phenyl)-4-oxobutan-2-yl)-5-(N-isopropyl-N-methylsulfamoyl)-2-((4-methoxyphenyl)thio)benzamide] and its analogs. We used purified human β2ARs, occupied by a high-affinity agonist, for the affinity-based screening of over 500 million distinct library compounds, which yielded Cmpd-6. It exhibits a low micro-molar affinity for the agonist-occupied β2AR and displays positive cooperativity with orthosteric agonists, thereby enhancing their binding to the receptor and ability to stabilize its active state. Cmpd-6 is cooperative with G protein and β-arrestin1 (a.k.a. arrestin2) to stabilize high-affinity, agonist-bound active states of the β2AR and potentiates downstream cAMP production and receptor recruitment of β-arrestin2 (a.k.a. arrestin3). Cmpd-6 is specific for the β2AR compared with the closely related β1AR. Structure–activity studies of select Cmpd-6 analogs defined the chemical groups that are critical for its biologic activity. We thus introduce the first small-molecule PAMs for the β2AR, which may serve as a lead molecule for the development of novel therapeutics. The approach described in this work establishes a broadly applicable proof-of-concept strategy for affinity-based discovery of small-molecule allosteric compounds targeting unique conformational states of GPCRs.

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“…According to the nitro reduction methods reported in the literature, [16][17][18] iron, zinc, and sodium dithionite were employed to prepare 2-chloro-5-aminoacetophenone. Compared with the catalytic hydrogenation using Pd-C/ H 2 , these methods could effectively avoid generation of the dechlorination byproduct and were suitable in situations without hydrogen gas.…”

Section: Resultsmentioning

confidence: 99%

An alternative method for the preparation of vismodegib: A tool for an undergraduate laboratory course

Bao,

Song,

Liu

et al. 2023

Journal of Chemical Research

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Vismodegib is the first hedgehog signaling pathway inhibitor approved by the Food and Drug Administration (FDA) for the treatment of basal-cell carcinoma. The reported methods for the preparation of vismodegib mostly require the employment of precious metal catalysts and phosphine ligands. An alternative low-cost method avoiding the employment of precious metal catalysts and phosphine ligand is developed to prepare vismodegib in a laboratory. The reported method is applied in an undergraduate experimental course to verify its reproducibility and to develop the experimental skills of students. Moreover, the teaching practice experiences are summed up to provide suggestions for the development of exploratory and further experimental courses.

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Synthesis of β₂-AR Agonist BI-167107

Cited by 4 publications

References 3 publications

Conformationally selective RNA aptamers allosterically modulate the β2-adrenoceptor

Conformationally selective RNA aptamers allosterically modulate the β2-adrenoceptor

Small-Molecule Positive Allosteric Modulators of the β2-Adrenoceptor Isolated from DNA-Encoded Libraries

An alternative method for the preparation of vismodegib: A tool for an undergraduate laboratory course

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Synthesis of β2-AR Agonist BI-167107

Cited by 4 publications

References 3 publications

Conformationally selective RNA aptamers allosterically modulate the β2-adrenoceptor

Conformationally selective RNA aptamers allosterically modulate the β2-adrenoceptor

Small-Molecule Positive Allosteric Modulators of the β2-Adrenoceptor Isolated from DNA-Encoded Libraries

An alternative method for the preparation of vismodegib: A tool for an undergraduate laboratory course

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Synthesis of β₂-AR Agonist BI-167107