Discovery and evaluation of novel FAAH inhibitors in neuropathic pain model

Bhuniya, Debnath; Kharul, Rajendra K.; Hajare, Atul; Shaikh, Nadim S.; Bhosale, Sandeep; Balwe, Sandip Gangadhar; Begum, Feroza; De, Siddhartha; Athavankar, Sonalee; Joshi, Dhananjay; Madgula, Vamsi L M; Joshi, Kaushal; Raje, Amol A.; Meru, Ashwinkumar V.; Magdum, Amol; Mookhtiar, Kasim A.; Barbhaiya, Rashmi H.

doi:10.1016/j.bmcl.2018.11.048

Cited by 28 publications

(14 citation statements)

References 49 publications

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“…42,43 However, pharmacological intervention is not without risk as has been demonstrated by the adverse psychiatric side effects of Rimonabant, a synthetic CB1 antagonist that was developed to treat obesity, 44,45 and the very serious adverse psychotic effects of the highly potent synthetic cannabinoid agonists colloquially termed ''Spice''. 46 It is perhaps worth noting that some of the most promising medicines targeting eCB signaling are based on using the natural cannabinoids from plants, including D9tetrahydrocannabinol and/or CBD, 47,48 or based on small molecule drugs that increase the levels of AEA 49,50 2-LG IS A PARTIAL AGONIST OF THE CB1 RECEPTOR or 2-AG. 51,52 In this context, strategies that increase 2-LG levels could have therapeutic potential as in some instances, they could introduce or maintain a moderate tone and/or mitigate against overactivation of the system.…”

Section: Discussionmentioning

confidence: 99%

2-Linoleoylglycerol Is a Partial Agonist of the Human Cannabinoid Type 1 Receptor that Can Suppress 2-Arachidonolyglycerol and Anandamide Activity

Williams

Doherty

2019

Cannabis and Cannabinoid Research

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Introduction: The cannabinoid type 1 (CB1) receptor and cannabinoid type 2 (CB2) receptor are widely expressed in the body and anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are their best characterized endogenous ligands. The diacylglycerol lipases (diacylglycerol lipase alpha and diacylglycerol lipase beta) not only synthesize essentially all the 2-AG in the body but also generate other monoacylglycerols, including 2linoleoylglycerol (2-LG). This lipid has been proposed to modulate endocannabinoid (eCB) signaling by protecting 2-AG from hydrolysis. However, more recently, 2-LG has been reported to be a CB1 antagonist. Methods: The effect of 2-LG on the human CB1 receptor activity was evaluated in vitro using a cell-based reporter assay that couples CB1 receptor activation to the expression of the b-lactamase enzyme. Receptor activity can then be measured by a b-lactamase enzymatic assay. Results: When benchmarked against 2-AG, AEA, and arachidonoyl-2¢-chloroethylamide (a synthetic CB1 agonist), 2-LG functions as a partial agonist at the CB1 receptor. The 2-LG response was potentiated by JZL195, a drug that inhibits the hydrolysis of monoacylglycerols. The 2-LG response was also fully inhibited by the synthetic CB1 antagonist AM251 and by the natural plant derived antagonist cannabidiol. 2-LG did not potentiate, and only blunted, the activity of 2-AG and AEA. Conclusions: These results support the hypothesis that 2-LG is a partial agonist at the human CB1 receptor and capable of modulating the activity of the established eCBs.

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Section: Discussionmentioning

confidence: 99%

2-Linoleoylglycerol Is a Partial Agonist of the Human Cannabinoid Type 1 Receptor that Can Suppress 2-Arachidonolyglycerol and Anandamide Activity

Williams

Doherty

2019

Cannabis and Cannabinoid Research

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“…A note of caution is the CC50 of PF-3845 to mammalian cells is even lower than its MIC against Mtb H37Rv, leaving it at a position unpropitious to become a TB drug candidate. Nevertheless, as tens of synthetic analogs of PF-3845 have been reported in literatures (29,41,42), the PF-3845 scaffold will serve as an excellent chemical probe to study the functions of bacterial and human PheRSs.…”

Section: Pf-3845 Does Not Inhibit Either Human Cytoplasmic or Mitochomentioning

confidence: 99%

Re-discovery of PF-3845 as a new chemical scaffold inhibiting phenylalanyl-tRNA synthetase inMycobacterium tuberculosis

Wang

Engelhart³

et al. 2020

Preprint

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Mycobacteria tuberculosis (Mtb) remains the deadliest pathogenic bacteria worldwide. The search for new antibiotics to treat drug-sensitive as well as drug-resistant tuberculosis has become a priority. The essential enzyme phenylalanyl-tRNA synthetase (PheRS) is an antibacterial drug target because of the large differences between bacterial and human PheRS counterparts. In a high-throughput screening of 2148 bioactive compounds, PF-3845, which is a known inhibitor of human fatty acid amide hydrolase (FAAH), was identified inhibiting Mtb PheRS at Ki ~0.73 0.055 M. The inhibition mechanism was studied with enzyme kinetics, protein structural modelling and crystallography, in comparison to a PheRS inhibitor of the noted phenyl-thiazolylurea-sulfonamide class. The 2.3- crystal structure of Mtb PheRS in complex with PF-3845 revealed its novel binding mode, in which a trifluoromethyl-pyridinylphenyl group occupies the Phe pocket while a piperidine-piperazine urea group binds into the ATP pocket through an interaction network enforced by a sulfate ion. It represents the first non-nucleoside bi-substrate competitive inhibitor of bacterial PheRS. PF-3845 inhibits the in vitro growth of Mtb H37Rv at ~24 M, and the potency of PF-3845 increased against Mtb pheS-FDAS, suggesting on target activity in mycobacterial whole cells. PF-3845 does not inhibit human cytoplasmic or mitochondrial PheRSs in biochemical assay, which can be explained from the crystal structures. Further elaboration of the piperidine-piperazine urea moiety by medicinal chemistry effort will produce potential antibacterial lead with improved selectivity on the cellular level.

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“…A cautionary note is that the CC 50 of PF-3845 to mammalian cells is even lower than its MIC against Mtb H37Rv, leaving it at a position unpropitious to become a TB drug candidate. Nevertheless, as tens of synthetic analogs of PF-3845 have been reported in the literatures (28,42,43), the PF-3845 scaffold can be used as an excellent chemical probe to study the function and evolution of bacterial and human PheRSs.…”

Section: Discussionmentioning

confidence: 99%

Rediscovery of PF-3845 as a new chemical scaffold inhibiting phenylalanyl-tRNA synthetase in Mycobacterium tuberculosis

Wang

Engelhart

et al. 2021

Journal of Biological Chemistry

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Mycobacterium tuberculosis (Mtb) remains the deadliest pathogenic bacteria worldwide. The search for new antibiotics to treat drug-sensitive as well as drug-resistant tuberculosis has become a priority. The essential enzyme phenylalanyl-tRNA synthetase (PheRS) is an antibacterial drug target because of the large differences between bacterial and human PheRS counterparts. In a high-throughput screening of 2148 bioactive compounds, PF-3845, which is a known inhibitor of human fatty acid amide hydrolase, was identified inhibiting Mtb PheRS at K i ∼ 0.73 ± 0.06 μM. The inhibition mechanism was studied with enzyme kinetics, protein structural modeling, and crystallography, in comparison to a PheRS inhibitor of the noted phenyl–thiazolylurea–sulfonamide class. The 2.3-Å crystal structure of Mtb PheRS in complex with PF-3845 revealed its novel binding mode, in which a trifluoromethyl–pyridinylphenyl group occupies the phenylalanine pocket, whereas a piperidine–piperazine urea group binds into the ATP pocket through an interaction network enforced by a sulfate ion. It represents the first non-nucleoside bisubstrate competitive inhibitor of bacterial PheRS. PF-3845 inhibits the in vitro growth of Mtb H37Rv at ∼24 μM, and the potency of PF-3845 increased against an engineered strain Mtb pheS–FDAS, suggesting on target activity in mycobacterial whole cells. PF-3845 does not inhibit human cytoplasmic or mitochondrial PheRS in biochemical assay, which can be explained from the crystal structures. Further medicinal chemistry efforts focused on the piperidine–piperazine urea moiety may result in the identification of a selective antibacterial lead compound.

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Discovery and evaluation of novel FAAH inhibitors in neuropathic pain model

Cited by 28 publications

References 49 publications

2-Linoleoylglycerol Is a Partial Agonist of the Human Cannabinoid Type 1 Receptor that Can Suppress 2-Arachidonolyglycerol and Anandamide Activity

2-Linoleoylglycerol Is a Partial Agonist of the Human Cannabinoid Type 1 Receptor that Can Suppress 2-Arachidonolyglycerol and Anandamide Activity

Re-discovery of PF-3845 as a new chemical scaffold inhibiting phenylalanyl-tRNA synthetase inMycobacterium tuberculosis

Rediscovery of PF-3845 as a new chemical scaffold inhibiting phenylalanyl-tRNA synthetase in Mycobacterium tuberculosis

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