Structure–activity relationships of the prototypical TRPM8 agonist icilin

Petrocellis, Luciano De; Ortar, Giorgio; Moriello, Aniello Schiano; Serum, Eric M.; Rusterholz, David B.

doi:10.1016/j.bmcl.2015.04.032

Cited by 16 publications

(10 citation statements)

References 52 publications

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“…In addition to scratching, we noted that calcipotriol-treated rats engage in 'wet dog shakes' . Systemic administration of icilin, an agonist of TRPA1 2,20,21 and TRPM8 22,23 , has also previously been reported to induce wet dog shakes in rodents 24,25 , although TRPA1′s contribution to this behavior is unclear 26 . To test whether calcipotriol-induced wet dog shakes could be TRPA1-dependent, we also quantified these behaviors.…”

Section: Examination Of Trpa1 Ko Rats In Models Of Nociception Acutementioning

confidence: 99%

Behavioral characterization of a CRISPR-generated TRPA1 knockout rat in models of pain, itch, and asthma

Reese¹,

Dourado²,

Anderson³

et al. 2020

Sci Rep

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The transient receptor potential (TRP) superfamily of ion channels has garnered significant attention by the pharmaceutical industry. In particular, TRP channels showing high levels of expression in sensory neurons such as TRPV1, TRPA1, and TRPM8, have been considered as targets for indications where sensory neurons play a fundamental role, such as pain, itch, and asthma. Modeling these indications in rodents is challenging, especially in mice. The rat is the preferred species for pharmacological studies in pain, itch, and asthma, but until recently, genetic manipulation of the rat has been technically challenging. Here, using CRISPR technology, we have generated a TRPA1 KO rat to enable more sophisticated modeling of pain, itch, and asthma. We present a detailed phenotyping of the TRPA1 KO rat in models of pain, itch, and asthma that have previously only been investigated in the mouse. With the exception of nociception induced by direct TRPA1 activation, we have found that the TRPA1 KO rat shows apparently normal behavioral responses in multiple models of pain and itch. Immune cell infiltration into the lung in the rat OVA model of asthma, on the other hand, appears to be dependent on TRPA1, similar to was has been observed in TRPA1 KO mice. Our hope is that the TRPA1 KO rat will become a useful tool in further studies of TRPA1 as a drug target.

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Section: Examination Of Trpa1 Ko Rats In Models Of Nociception Acutementioning

confidence: 99%

Behavioral characterization of a CRISPR-generated TRPA1 knockout rat in models of pain, itch, and asthma

Reese¹,

Dourado²,

Anderson³

et al. 2020

Sci Rep

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“…The group of De Petrocellis explored the preparation of new analogues by modification of the pyrimidin-2-one central scaffold of icilin in an attempt to improve the therapeutic potential. 146 Work at the three rings of the icilin molecule demonstrated very narrow limits for modification. SAR studies point to the importance of the presence and position of the o-OH and m-NO 2 substituents on the distal phenyl groups.…”

Section: Trpm8 Agonist Chemotypesmentioning

confidence: 99%

“…Both a lower homologue of the central ring and conformationally restricted tricyclic derivatives were totally inactive. 146 Structurally unrelated pyrimidine derivatives, exemplified by compound 9, produce cooling effects on skin and mucous membranes through the interaction with the TRPM8 receptor (submicromolar potencies). 147 5.3.…”

Section: Trpm8 Agonist Chemotypesmentioning

confidence: 99%

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

et al. 2016

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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.

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“…Apart from its role in thermosensation, acute activation of TRPM8 can have analgesic effects [29] suggesting that neuronal TRPM8 may play a neurogenic anti-inflammatory role. Very recently it has been shown that the synthetic TRPM8 agonist icilin (i) has a potent anti-inflammatory effect, and (ii) inhibits E2F1 transcription factor-mediated cell cycle regulatory programs in prostate cancer [30], thus suggesting the potential relevance of icilin and 'icilin-like' compounds as therapeutic tools for the treatment of a variety of pathological conditions [31].…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effect of positively charged triazine antagonists of prokineticin receptors on the transient receptor vanilloid type-1 (TRPV1) channel

Petrocellis

Moriello

Byun

et al. 2015

Pharmacological Research

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Four positively charged compounds, previously shown to produce analgesic activity by interacting with prokineticin receptor or T-type calcium channels, were tested for their ability to inhibit capsaicin-induced elevation of intracellular Ca(2+) in HEK-293 cells stably transfected with the human recombinant TRPV1, with the goal of identifying novel TRPV1 open-pore inhibitors. KYS-05090 showed the highest potency as a TRPV1 antagonist, even higher than that of the open-pore triazine inhibitor 8aA. The latter showed quite remarkable agonist/desensitizer activity at the rat recombinant TRPM8 channel. The activity of KYS-05090 and the other compounds was selective because none of these compounds was able to modulate the rat TRPA1 channel. Open-pore inhibitors of TRPV1 may be a new class of multi-target analgesics with lesser side effects, such as loss of acute pain sensitivity and hyperthermia, than most TRPV1 antagonists developed so far.

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Structure–activity relationships of the prototypical TRPM8 agonist icilin

Cited by 16 publications

References 52 publications

Behavioral characterization of a CRISPR-generated TRPA1 knockout rat in models of pain, itch, and asthma

Behavioral characterization of a CRISPR-generated TRPA1 knockout rat in models of pain, itch, and asthma

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

Inhibitory effect of positively charged triazine antagonists of prokineticin receptors on the transient receptor vanilloid type-1 (TRPV1) channel

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