Novel Triaryl Sulfonamide Derivatives as Selective Cannabinoid Receptor 2 Inverse Agonists and Osteoclast Inhibitors: Discovery, Optimization, and Biological Evaluation

Yang, Peng; Wang, Liping; Feng, Rentian; Almehizia, Abdulrahman A.; Tong, Qin; Myint, Kyaw-Zeyar; Ouyang, Qin; Alqarni, Mohammed H.; Wang, Lirong; Xie, Xiang‐Qun

doi:10.1021/jm3017464

Cited by 39 publications

(48 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among these 10 compounds, two compounds, NSC273939 51 and NSC273940, inhibited [ 3 H]CP-55,940 binding to CB2 with K i values of 0.192 and 0.195 μ M, respectively. NSC273936, NSC402300, and NSC618804 inhibited [ 3 H]CP-55,940 binding to hCB2 with K i values of 0.346, 0.398, and 0.656 μ M, respectively.…”

Section: Resultsmentioning

confidence: 99%

Difference and Influence of Inactive and Active States of Cannabinoid Receptor Subtype CB2: From Conformation to Drug Discovery

Feng

et al. 2016

J. Chem. Inf. Model.

Self Cite

View full text Add to dashboard Cite

Cannabinoid receptor 2 (CB2), a G protein-coupled receptor (GPCR), is a promising target for the treatment of neuropathic pain, osteoporosis, immune system, cancer, and drug abuse. The lack of an experimental three-dimensional CB2 structure has hindered not only the development of studies of conformational differences between the inactive and active CB2 but also the rational discovery of novel functional compounds targeting CB2. In this work, we constructed models of both inactive and active CB2 by homology modeling. Then we conducted two comparative 100 ns molecular dynamics (MD) simulations on the two systems—the active CB2 bound with both the agonist and G protein and the inactive CB2 bound with inverse agonist—to analyze the conformational difference of CB2 proteins and the key residues involved in molecular recognition. Our results showed that the inactive CB2 and the inverse agonist remained stable during the MD simulation. However, during the MD simulations, we observed dynamical details about the breakdown of the “ionic lock” between R1313.50 and D2406.30 as well as the outward/inward movements of transmembrane domains of the active CB2 that bind with G proteins and agonist (TM5, TM6, and TM7). All of these results are congruent with the experimental data and recent reports. Moreover, our results indicate that W2586.48 in TM6 and residues in TM4 (V1644.56–L1694.61) contribute greatly to the binding of the agonist on the basis of the binding energy decomposition, while residues S180–F183 in extracellular loop 2 (ECL2) may be of importance in recognition of the inverse agonist. Furthermore, pharmacophore modeling and virtual screening were carried out for the inactive and active CB2 models in parallel. Among all 10 hits, two compounds exhibited novel scaffolds and can be used as novel chemical probes for future studies of CB2. Importantly, our studies show that the hits obtained from the inactive CB2 model mainly act as inverse agonist(s) or neutral antagonist(s) at low concentration. Moreover, the hit from the active CB2 model also behaves as a neutral antagonist at low concentration. Our studies provide new insight leading to a better understanding of the structural and conformational differences between two states of CB2 and illuminate the effects of structure on virtual screening and drug design.

show abstract

Section: Resultsmentioning

confidence: 99%

Difference and Influence of Inactive and Active States of Cannabinoid Receptor Subtype CB2: From Conformation to Drug Discovery

Feng

et al. 2016

J. Chem. Inf. Model.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The cannabinoid receptor 2 (CB2) is an important protein in the endocannabinoid system that has been well recognized for its role in regulating the immune response [43–46]. It has therefore been proposed as an attractive therapeutic target for treating a range of diseases involving inflammation [47] and auto-immune disorders including neurodegenerative diseases and bone loss [48].…”

Section: Discussionmentioning

confidence: 99%

Multi-Functional Diarylurea Small Molecule Inhibitors of TRPV1 with Therapeutic Potential for Neuroinflammation

Feng

Pearce

Zhang

et al. 2016

AAPS J

Self Cite

View full text Add to dashboard Cite

Transient receptor potential vanilloid type 1 (TRPV1), a heat-sensitive calcium channel protein, contributes to inflammation as well as to acute and persistent pain. Since TRPV1 occupies a central position in pathways of neuronal inflammatory signaling, it represents a highly attractive potential therapeutic target for neuroinflammation. In the present work, we have in silico identified a series of diarylurea analogues for hTRPV1, of which 11 compounds showed activity in the nanomolar to micromolar range as validated by in vitro biological assays. Then, we utilized molecular docking to explore the detailed interactions between TRPV1 and the compounds to understand the contributions of the different substituent groups. Tyr511, Leu518, Leu547, Thr550, Asn551, Arg557, and Leu670 were important for the recognition of the small molecules by TRPV1. A hydrophobic group in R2 or a polar/hydrophilic group in R1 contributed significantly to the activities of the antagonists at TRPV1. In addition, the subtle different binding pose of meta-chloro in place of para-fluoro in the R2 group converted antagonism into partial agonism, as was predicted by our short-term molecular dynamics (MD) simulation and validated by bioassay. Importantly, compound 15, one of our best TRPV1 inhibitors, also showed potential binding affinity (1.39 µM) at cannabinoid receptor 2 (CB2), which is another attractive target for immune-inflammation diseases. Furthermore, compound 1 and its diarylurea analogues were predicted to target the C-X-C chemokine receptor 2 (CXCR2), although bioassay validation of CXCR2 with these compounds still needs to be performed. This prediction from the modeling is of interest, since CXCR2 is also a potential therapeutic target for chronic inflammatory diseases. Our findings provide novel strategies to develop a small molecule inhibitor to simultaneously target two or more inflammation-related proteins for the treatment of a wide range of inflammatory disorders including neuroinflammation and neurodegenerative diseases with potential synergistic effect.

show abstract

“…Molecular weight distribution and composition of the polymers were determined using GPC and 1 H NMR spectroscopy, respectively. The acetylene groups present on polymer 5 were used for click reaction with various azide derivatives under copper catalysed condition to synthesize target block copolymers P1-P4 in quantitative yields [31][32][33][34][35].…”

Section: Resultsmentioning

confidence: 99%

Synthesis of amphiphilic block copolyamines via click reaction

Goud

Dsouza

Valiyaveettil

2015

European Polymer Journal

View full text Add to dashboard Cite

Novel Triaryl Sulfonamide Derivatives as Selective Cannabinoid Receptor 2 Inverse Agonists and Osteoclast Inhibitors: Discovery, Optimization, and Biological Evaluation

Cited by 39 publications

References 42 publications

Difference and Influence of Inactive and Active States of Cannabinoid Receptor Subtype CB2: From Conformation to Drug Discovery

Difference and Influence of Inactive and Active States of Cannabinoid Receptor Subtype CB2: From Conformation to Drug Discovery

Multi-Functional Diarylurea Small Molecule Inhibitors of TRPV1 with Therapeutic Potential for Neuroinflammation

Synthesis of amphiphilic block copolyamines via click reaction

Contact Info

Product

Resources

About