Design, synthesis, and binding mode prediction of 2-pyridone-based selective CB2 receptor agonists

Kusakabe, Ken‐ichi; Tada, Yukio; Iso, Y.; Sakagami, Masahiro; Morioka, Yasuhide; Chomei, Nobuo; Shinonome, Satomi; Kawamoto, Keiko; Takenaka, Hideyuki; Yasui, Kiyoshi; Hamana, Hiroshi; Hanasaki, Kohji

doi:10.1016/j.bmc.2013.01.006

Cited by 35 publications

(18 citation statements)

References 36 publications

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“…The binding pocket of the CB2 model was verified by recent docking results, 58−60 which was in agreement with most other GPCRs. Moreover, we found that the binding pocket can be extended into helix IV via a narrow “crevice”.…”

Section: Resultssupporting

confidence: 77%

Modeling, Molecular Dynamics Simulation, and Mutation Validation for Structure of Cannabinoid Receptor 2 Based on Known Crystal Structures of GPCRs

Feng

Alqarni

Yang

et al. 2014

J. Chem. Inf. Model.

100

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The cannabinoid receptor 2 (CB2) plays an important role in the immune system. Although a few of GPCRs crystallographic structures have been reported, it is still challenging to obtain functional transmembrane proteins and high resolution X-ray crystal structures, such as for the CB2 receptor. In the present work, we used 10 reported crystal structures of GPCRs which had high sequence identities with CB2 to construct homology-based comparative CB2 models. We applied these 10 models to perform a prescreen by using a training set consisting of 20 CB2 active compounds and 980 compounds randomly selected from the National Cancer Institute (NCI) database. We then utilized the known 170 cannabinoid receptor 1 (CB1) or CB2 selective compounds for further validation. Based on the docking results, we selected one CB2 model (constructed by β1AR) that was most consistent with the known experimental data, revealing that the defined binding pocket in our CB2 model was well-correlated with the training and testing data studies. Importantly, we identified a potential allosteric binding pocket adjacent to the orthosteric ligand-binding site, which is similar to the reported allosteric pocket for sodium ion Na+ in the A2AAR and the δ-opioid receptor. Our studies in correlation of our data with others suggested that sodium may reduce the binding affinities of endogenous agonists or its analogs to CB2. We performed a series of docking studies to compare the important residues in the binding pockets of CB2 with CB1, including antagonist, agonist, and our CB2 neutral compound (neutral antagonist) XIE35-1001. Then, we carried out 50 ns molecular dynamics (MD) simulations for the CB2 docked with SR144528 and CP55940, respectively. We found that the conformational changes of CB2 upon antagonist/agonist binding were congruent with recent reports of those for other GPCRs. Based on these results, we further examined one known residue, Val1133.32, and predicted two new residues, Phe183 in ECL2 and Phe2817.35, that were important for SR144528 and CP55940 binding to CB2. We then performed site-directed mutation experimental study for these residues and validated the predictions by radiometric binding affinity assay.

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Section: Resultssupporting

confidence: 77%

Modeling, Molecular Dynamics Simulation, and Mutation Validation for Structure of Cannabinoid Receptor 2 Based on Known Crystal Structures of GPCRs

Feng

Alqarni

Yang

et al. 2014

J. Chem. Inf. Model.

100

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“…261 In the case where amide linkages exist between the aryl groups, S193(5.42) does act as a H-bond donor. 324,325 These interactions may help to provide nsight into why di-protected triaryls do not behave as their di-deprotected counterparts.…”

Section: C-1 Hydroxyl Benzchromene Oxygen and (Optional) C-6 Hydroxylmentioning

confidence: 99%

“…261 In the case where amide linkages exist between the aryl groups, it is suggested that S193(5.42) does act as a H-bond donor. 324,325 4.6.2.2. Hydrophobic and π-π stacking.…”

Section: Interactions With the Cb2 Lbpmentioning

confidence: 99%

“…261 More recent 2-pyridone derivatives add additional residues to the binding pocket for π-π stacking, namely Y190(5.39) and F281(7.35) along with C288(7.42). 324,325 For the 2-pyridone analog containing N-butyl, there is a proposed hydrophobic interaction with I198(5.47). 325 Though little data exists, it is suggested that SR-144528 (a CB2-selective inverse agonist) has interaction with W194(5.43) and F197(5.46), 338 which may play a role in stabilizing the inactive state and impart inverse agonist activity.…”

Section: Hydrophobic and π-π Stackingmentioning

confidence: 99%

“…261 More recent 2-pyridone derivatives add additional residues to the binding pocket for π-π stacking, namely Y190(5.39) and F281(7.35) along with a C288(7.42) residue. 324,325 For the 2-pyridone analog containing N-butyl, there involves a hydrophobic interaction with I198(5.47). hypothesize that the binding mode for the hexahydro series is more similar to THC, in that the ABC ring occupies the tricyclic (ABC ring) pocket of the LBP and the C-3 substituents project into the major pocket.…”

Section: Interactions With the Cb2 Lbpmentioning

confidence: 99%

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Functional Activity and Switching of Novel Cannabinergic Ligands

Koertge¹

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Expanding the Utility of Inexpensive Pyridine‐N‐oxide Directing Group for the Site‐selective sp²/sp³γ‐C−H and sp²δ‐C−H Functionalization of Carboxamides

et al. 2022

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We have shown our efforts toward expanding the utility of the relatively inexpensive pyridine-N-oxide directing group in the Pd(II)-catalyzed site-selective γ-C(sp 2 )À H, γ-C(sp 3 )À H and δ-C(sp 2 )À H functionalization. The functionalization βÀ CÀ H bonds using bidentate directing group (DG) pyridine-N-oxide which operates through the N,O-coordination mode has been well documented in the literature. However, there exist rare reports dealing with the functionalization of remote sp 2 /sp 3 γand δ-CÀ H bonds of carboxamides assisted by the bidentate directing groups operating via the N,O-coordination. In this paper, the scope of pyridine-N-oxide DG was examined for accomplishing the siteselective (mono) γ-C(sp 2 )À H arylation in substrates containing competitive C(sp 3 )À H and C(sp 2 )À H bonds. The investigation has enabled to assemble a library of pyridine-N-oxide-based biarylacetamides, heteroaryl-based biaryl carboxamides, tricyclic quinolones, arylheteroarylmethanes, biaryl-based aliphatic carboxamides and mono (ortho) arylated phenylglycine derivatives. In general, biaryl derivatives and in particular, arylacetamide, arylacetic acid derivatives and pyridine-N-oxide (2-aminopyridyl) motifs are medicinally relevant classes of compounds. This work enabled the assembling of a library of the above-mentioned types of compounds through the pyridine-N-oxide directing groupaided site-selective sp 2 /sp 3 γ-CÀ H and sp 2 δ-CÀ H functionalization of carboxamides.

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Design, synthesis, and binding mode prediction of 2-pyridone-based selective CB2 receptor agonists

Cited by 35 publications

References 36 publications

Modeling, Molecular Dynamics Simulation, and Mutation Validation for Structure of Cannabinoid Receptor 2 Based on Known Crystal Structures of GPCRs

Modeling, Molecular Dynamics Simulation, and Mutation Validation for Structure of Cannabinoid Receptor 2 Based on Known Crystal Structures of GPCRs

Functional Activity and Switching of Novel Cannabinergic Ligands

Expanding the Utility of Inexpensive Pyridine‐N‐oxide Directing Group for the Site‐selective sp²/sp³γ‐C−H and sp²δ‐C−H Functionalization of Carboxamides

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Design, synthesis, and binding mode prediction of 2-pyridone-based selective CB2 receptor agonists

Cited by 35 publications

References 36 publications

Modeling, Molecular Dynamics Simulation, and Mutation Validation for Structure of Cannabinoid Receptor 2 Based on Known Crystal Structures of GPCRs

Modeling, Molecular Dynamics Simulation, and Mutation Validation for Structure of Cannabinoid Receptor 2 Based on Known Crystal Structures of GPCRs

Functional Activity and Switching of Novel Cannabinergic Ligands

Expanding the Utility of Inexpensive Pyridine‐N‐oxide Directing Group for the Site‐selective sp2/sp3γ‐C−H and sp2δ‐C−H Functionalization of Carboxamides

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Product

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Expanding the Utility of Inexpensive Pyridine‐N‐oxide Directing Group for the Site‐selective sp²/sp³γ‐C−H and sp²δ‐C−H Functionalization of Carboxamides