In vitro characterization of the thermoneutral transient receptor potential vanilloid-1 (TRPV1) inhibitor GRTE16523

Damann, Nils; Bahrenberg, Gregor; Stockhausen, Hannelore; Habermann, Christopher; Lesch, B.; Frank-Foltyn, Robert; Lee, Jeeyeon; Ann, Jihyae; Christoph, Thomas

doi:10.1016/j.ejphar.2020.172934

Cited by 12 publications

(10 citation statements)

References 43 publications

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“…It remains to be seen whether these molecules — or other ‘thermoneutral’ antagonists, like GRTE16523 (ref. 63 ) — can demonstrate meaningful analgesic activity in the clinic. Ultimately, it will probably be easier to dissociate beneficial heat sensing from therapeutic inhibition of TRPV1 activity by targeted antagonist delivery because most, if not all, inhibitors of TRPV1 activation will inhibit heat sensing.…”

Section: Pain: Trp Channels As Analgesic Targetsmentioning

confidence: 99%

Advances in TRP channel drug discovery: from target validation to clinical studies

Koivisto

Belvisi

Gaudet

et al. 2021

Nat Rev Drug Discov

332

171

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Transient receptor potential (TRP) channels are multifunctional signalling molecules with many roles in sensory perception and cellular physiology. Therefore, it is not surprising that TRP channels have been implicated in numerous diseases, including hereditary disorders caused by defects in genes encoding TRP channels (TRP channelopathies). Most TRP channels are located at the cell surface, which makes them generally accessible drug targets. Early drug discovery efforts to target TRP channels focused on pain, but as our knowledge of TRP channels and their role in health and disease has grown, these efforts have expanded into new clinical indications, ranging from respiratory disorders through neurological and psychiatric diseases to diabetes and cancer. In this Review, we discuss recent findings in TRP channel structural biology that can affect both drug development and clinical indications. We also discuss the clinical promise of novel TRP channel modulators, aimed at both established and emerging targets. Last, we address the challenges that these compounds may face in clinical practice, including the need for carefully targeted approaches to minimize potential side-effects due to the multifunctional roles of TRP channels.

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Section: Pain: Trp Channels As Analgesic Targetsmentioning

confidence: 99%

Advances in TRP channel drug discovery: from target validation to clinical studies

Koivisto

Belvisi

Gaudet

et al. 2021

Nat Rev Drug Discov

332

171

View full text Add to dashboard Cite

show abstract

“…To preliminarily evaluate the pharmacological function of the designed ligands on the TRPV1 receptor, FlexStation 3 multifunction microplate reader assays were performed in h TRPV1 transiently expressed human embryonic kidney (HEK293) cells . We measured the activation capacity of capsaicin (EC 50 = 29 ± 2 nM, Figure S1) and used 100 nM capsaicin to ensure maximal opening of the TRPV1 channel . The agonistic efficacy of the compounds was determined by comparison with capsaicin (100 nM) as a positive control.…”

Section: Resultsmentioning

confidence: 99%

“…24 We measured the activation capacity of capsaicin (EC 50 = 29 ± 2 nM, Figure S1) and used 100 nM capsaicin to ensure maximal opening of the TRPV1 channel. 25 The agonistic efficacy of the compounds was determined by comparison with capsaicin (100 nM) as a positive control. The antagonistic ability of the compounds was determined by inhibiting the activation of capsaicin (100 nM).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Discovery of Potent and Selective Transient Receptor Potential Vanilloid 1 (TRPV1) Agonists with Analgesic Effects In Vivo Based on the Functional Conversion Induced by Altering the Orientation of the Indazole Core

Liang

Qiao

Zhou³

et al. 2022

J. Med. Chem.

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Transient receptor potential vanilloid 1 (TRPV1) is a promising target for developing antinociceptive agents. Here, we report the synthesis of N-indazole-4-aryl piperazine carboxamide analogues as TRPV1 modulators. The structure–activity relationship (SAR) reveals that substituting indazole at the 5-/6-position leads to TRPV1 agonism, whereas the 4- and 7-positions of indazole obtain mild antagonism and loss of activity, respectively. The whole-cell clamp patch assay shows that 28 is a potent and selective TRPV1 agonist and it relieves inflammatory and thermal pain by desensitizing the native TRPV1 current in the dorsal root ganglion (DRG) in mice. Additionally, site-directed mutagenesis combined with molecular docking shows an important hydrogen interaction between Arg557 and the indazole of 28. Taken together, our findings provide insight into TRPV1 agonism–antagonism conversion based on the interaction between indazole and Arg557, which provides a strategy to obtain new TRPV1 agonists by structural modification of antagonists. Compound 28 may be used as a lead compound for further optimization.

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“…Moreover, TRPV1 inhibitors are known to cause hyperthermia in WT mice, which is an undesired side effect of such compounds [28,29]. Further studies using thermoneutral TRPV1 inhibitors [30] are required to clarify the role of TRPV1 in the regulation of metabolic activity. Also, several of these studies have evaluated metabolic activity only acutely in TRPV1 À/À mice, while the results presented in this study were conducted for 48 h after 32 weeks of feeding NCD or HFD.…”

Section: Discussionmentioning

confidence: 99%

Mice lacking endogenous TRPV1 express reduced levels of thermogenic proteins and are susceptible to diet‐induced obesity and metabolic dysfunction

et al. 2021

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Transient receptor potential vanilloid subfamily 1 (TRPV1) is a non-selective cation channel protein expressed in neuronal and non-neuronal cells. Although TRPV1 is implicated in thermogenesis and diet-induced obesity (DIO), its precise role remains controversial. TRPV1 À/À mice are protected from DIO, while TRPV1 activation enhances thermogenesis to prevent obesity. To reconcile this, we fed wild-type and TRPV1 À/À mice for 32 weeks with normal chow or a high-fat diet and analyzed the weight gain, metabolic activities, and thermogenic protein expression in white and brown fats. TRPV1 À/À mice became obese, exhibited reduced locomotor activity, reduced energy expenditure, enhanced hepatic steatosis, and decreased thermogenic protein expression in adipose tissues. Our data reveal that lack of TRPV1 does not prevent obesity, but rather enhances metabolic dysfunction.

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In vitro characterization of the thermoneutral transient receptor potential vanilloid-1 (TRPV1) inhibitor GRTE16523

Cited by 12 publications

References 43 publications

Advances in TRP channel drug discovery: from target validation to clinical studies

Advances in TRP channel drug discovery: from target validation to clinical studies

Discovery of Potent and Selective Transient Receptor Potential Vanilloid 1 (TRPV1) Agonists with Analgesic Effects In Vivo Based on the Functional Conversion Induced by Altering the Orientation of the Indazole Core

Mice lacking endogenous TRPV1 express reduced levels of thermogenic proteins and are susceptible to diet‐induced obesity and metabolic dysfunction

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