Discovery of a Selective TRPM8 Antagonist with Clinical Efficacy in Cold-Related Pain

Andrews, M. D.; Forselles, Kerry af; Beaumont, Kevin; Galan, Sébastien R. G.; Glossop, Paul A.; Grenie, Mathilde; Jessiman, Alan S.; Kenyon, Amy S.; Lunn, Graham; Maw, Graham N.; Owen, Robert M.; Pryde, David C.; Roberts, Dannielle F.; Tran, Thien Duc

doi:10.1021/ml500479v

Cited by 68 publications

(51 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Inhibition of TRPM8 by its selective antagonist, PF‐05105679 (27), was capable of reversing menthol‐induced increases in UCP‐1 expression in IWs (Fig. 5 E ), as well as forskolin‐activated uncoupled respiration in menthol‐primed cells (Fig.…”

Section: Methodsmentioning

confidence: 98%

See 1 more Smart Citation

TRP channels in brown and white adipogenesis from human progenitors: new therapeutic targets and the caveats associated with the common antibiotic, streptomycin

et al. 2017

View full text Add to dashboard Cite

Transient receptor potential (TRP) channels are polymodal cell sensors responding to diverse stimuli and widely implicated in the developmental programs of numerous tissues. The evidence for an involvement of TRP family members in adipogenesis, however, is scant. We present the first comprehensive expression profile of all known 27 human TRP genes in mesenchymal progenitors cells during white or brown adipogenesis. Using positive trilineage differentiation as an exclusion criterion, TRP polycystic (P)3, and TPR melastatin (M)8 were found to be uniquely adipospecific. Knockdown of TRPP3 repressed the expression of the brown fat signature genes uncoupling protein (UCP)-1 and peroxisome proliferator-activated receptor γ coactivator (PGC)-1α as well as attenuated forskolin-stimulated uncoupled respiration. However, indices of generalized adipogenesis, such as lipid droplet morphology and fatty acid binding protein (FAPB)-4 expression, were not affected, indicating a principal mitochondrial role of TRPP3. Conversely, activating TRPM8 with menthol up-regulated UCP-1 expression and augmented uncoupled respiration predominantly in white adipocytes (browning), whereas streptomycin antagonized TRPM8-mediated calcium entry, downregulated UCP-1 expression, and mitigated uncoupled respiration; menthol was less capable of augmenting uncoupled respiration (thermogenesis) in brown adipocytes. TRPP3 and TRPM8 hence appear to be involved in the priming of mitochondria to perform uncoupled respiration downstream of adenylate cyclase. Our results also underscore the developmental caveats of using antibiotics in adipogenic studies.-Goralczyk, A., van Vijven, M., Koch, M., Badowski, C., Yassin, M. S., Toh, S.-A., Shabbir, A., Franco-Obregón, A., Raghunath, M. TRP channels in brown and white adipogenesis from human progenitors: new therapeutic targets and the caveats associated with the common antibiotic, streptomycin.

show abstract

Section: Methodsmentioning

confidence: 98%

“…The TRPM8 antagonist, PF-05105679 (Pfizer; Sigma-Aldrich) (27) was added to the culture medium during WA and BA differentiation, commencing from the second week of differentiation (t 3 ) until the end of the experiment (t 5 ) (Supplemental Fig. 1D).…”

Section: Trpm8 Inhibition During Wa and Ba Differentiationmentioning

confidence: 99%

TRP channels in brown and white adipogenesis from human progenitors: new therapeutic targets and the caveats associated with the common antibiotic, streptomycin

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Based on the above rationale, new TRPM8‐modulating molecules have been developed and characterized in the last several years (for excellent tables summarizing older or more commonly used TRPM8 agonists and antagonists see and). Recent examples of novel TRPM8 modulators include compounds 12 (inhibitor) and 21 (activator), and the blockers PF‐05105679, AMG2850, compound 45 (this compound is the same as AMG1161 in), RQ‐00203078, another compound 12, and DFL23448 . Interestingly, a recent report from a team at Amgen used commercially available TRPM8 antibodies that recognize epitopes on the extracellular surface as antagonists to block channel function .…”

Section: Trpm8 As a Therapeutic Target For Non‐headache Disordersmentioning

confidence: 99%

TRPM8 and Migraine

Dussor

Cao

2016

Headache

View full text Add to dashboard Cite

Migraine is among the most common diseases on earth and one of the most disabling, the latter due in large part to poor treatment efficacy. Development of new therapeutics is dependent on the identification of mechanisms contributing to migraine and discovery of targets for new drugs. Numerous genome-wide association studies (GWAS) have implicated the transient receptorpotential M8 (TRPM8) channel in migraine. This channel is predominantly expressed on peripheral sensory neurons and is known as the sensor for cold temperature in cutaneous tissue but is also expressed on deep visceral afferents where cold is not likely a stimulus. Consequently, a number of alternative endogenous agonists have been proposed. Apart from its role in cold sensation, TRPM8 also contributes to cold allodynia after nerve injury or inflammation, and it is necessary for cooling/menthol-based analgesia. How it might contribute to migraine is less clear. The purpose of this review is to discuss the anatomical and physiological mechanisms by which meningeal TRPM8 may play a role in migraine as well as the potential of TRPM8 as a therapeutic target. TRPM8 is expressed on sensory afferents innervating the meninges, and these neurons are subject to developmental changes that may influence their contribution to migraine. As in viscera, meningeal TRPM8 channels are unlikely to be activated by temperature fluctuations and their endogenous ligands remain unknown. Preclinical migraine studies show that activation of meningeal TRPM8 by exogenous agonists can both cause and alleviate headache behaviors, depending on whether other meningeal afferents concurrently receive noxious stimuli. This is reminiscent of the fact that cold can trigger migraine in humans but menthol can also alleviate headache. We propose that both TRPM8 agonists and antagonists may be potential therapeutics,

show abstract

“…189 The prototype N-(2-thienylmethyl) derivative (AMTB, 40, IC 50 = 8 nM, Figure 12 The HTS screening of the Pfizer in house collection allowed the identification of another tertiary amide derivative with weak inhibitory properties of TRPM8 receptors, which upon optimization resulted in the quinolin-3-carboxamide derivative PF-05105679 (43). 192 Modifications at the acidic group resulted in reduced potency, while at the other benzylic residue only the incorporation of a m-chlorine atom is well tolerated. Its potency against TRPM8 was confirmed by patch-clamp electrophysiology studies, and selectivity was assessed through evaluation in a set of different receptors, enzymes and ion channels, including related thermoreceptors (TRPV1 and TRPA1) and hERG.…”

Section: Tertiary Amide Derivativesmentioning

confidence: 99%

Transient Receptor Potential Melastatin 8 Channel (TRPM8) Modulation: Cool Entryway for Treating Pain and Cancer

et al. 2016

View full text Add to dashboard Cite

Abstract. TRPM8 ion channels, the primary cold sensors in humans, are activated by innocuous cooling (< 28 ºC) and cooling compounds (menthol, icilin), and are implicated in sensing unpleasant cold stimuli, as well as in mammalian thermoregulation. Over-expression of these thermoregulators in prostate cancer and in other life-threatening tumors, along with their contribution to an increasing number of pathological conditions, opens a plethora of medicinal chemistry opportunities to develop receptor modulators. This Perspective seeks to compile current known modulators for this ion channel, since both agonists and antagonists may be useful for the treatment of most TRPM8-mediated pathologies. We primarily focus on SAR data for the different families of compounds and the pharmacological properties of the most promising ligands. Furthermore, we also address the knowledge about the channel structure, although still in its infancy, and the role of the TRPM8 protein signalplex to channel function and dysfunction. We finally outline the potential future prospects of the challenging TRPM8 drug discovery field.

show abstract

Discovery of a Selective TRPM8 Antagonist with Clinical Efficacy in Cold-Related Pain

Cited by 68 publications

References 34 publications

TRP channels in brown and white adipogenesis from human progenitors: new therapeutic targets and the caveats associated with the common antibiotic, streptomycin

TRP channels in brown and white adipogenesis from human progenitors: new therapeutic targets and the caveats associated with the common antibiotic, streptomycin

TRPM8 and Migraine

Transient Receptor Potential Melastatin 8 Channel (TRPM8) Modulation: Cool Entryway for Treating Pain and Cancer

Contact Info

Product

Resources

About