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Identification of a Novel TRPM8 Agonist from Nutmeg: A Promising Cooling Compound.

ABSTRACT: The transient receptor potential melastatin 8 (TRPM8) ion channel is the primary receptor for innocuous cold stimuli (<28 °C) in humans. TRPM8 agonists such as l-(-)-menthol are widely used as flavors and additives to impart briskness, in addition to medicinal uses for inflammation and pain. Though various natural and synthetic agonists have been explored, only few natural compounds are known. We report herein the identification and characterization of the novel neolignan agonist erythro- and threo-?8'-7-ethoxy-4-hydroxy-3,3',5'-trimethoxy-8-O-4'-neolignan (1) with an EC50 of 0.332 ?M, which was isolated from a well-known spice, nutmeg (Myristica fragrans Houtt.). Structure activity relationships are also disclosed, showing that the 7-d-menthoxy derivative is the most potent agonist (EC50 = 11 nM). The combination of 1 and l-(-)-menthol has an additive effect, suggesting that neolignan compounds interact with TRPM8 at different sites from those of l-(-)-menthol.

SUBMITTER: Shirai T

PROVIDER: S-EPMC5512136 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Identification of a Novel TRPM8 Agonist from Nutmeg: A Promising Cooling Compound.

Shirai Tomohiro T Kumihashi Kentaro K Sakasai Mitsuyoshi M Kusuoku Hiroshi H Shibuya Yusuke Y Ohuchi Atsushi A

ACS medicinal chemistry letters 20170531 7

The transient receptor potential melastatin 8 (TRPM8) ion channel is the primary receptor for innocuous cold stimuli (<28 °C) in humans. TRPM8 agonists such as <i>l</i>-(-)-menthol are widely used as flavors and additives to impart briskness, in addition to medicinal uses for inflammation and pain. Though various natural and synthetic agonists have been explored, only few natural compounds are known. We report herein the identification and characterization of the novel neolignan agonist <i>eryth ...[more]

PMID: 28740604

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Project description:BackgroundPhysical cooling of the eye surface relieves ocular discomfort, but translating this event to drug treatment of dry eye discomfort not been studied. Here, we synthesized a water-soluble TRPM8 receptor agonist called cryosim-3 (C3, 1-diisopropylphosphorylnonane) which selectively activates TRPM8 (linked to cooling) but not TRPV1 or TRPA1 (linked to nociception) and tested C3 in subjects with mild forms of dry eye disease.MethodsA set of 1-dialkylphosphoryalkanes were tested for activation of TRPM8, TRPV1 and TRPA1 receptors in transfected cells. The bioactivity profiles were compared by perioral, topical, and intravenous delivery to anesthetized rats. The selected lead candidate C3 or vehicle (water) was applied with a cotton gauze pad to upper eyelids of patients with dry eye disease (n = 30). Cooling sensation, tear film break-up time (TBUT), basal tear secretion, and corneal staining were evaluated. C3 was then applied four times daily for 2 weeks to patients using a pre-loaded single unit applicator containing 2 mg/mL of C3 in water (n = 20) or water only. TBUT, basal tear secretion, and corneal staining, and three questionnaires surveys of ocular discomfort (VAS scale, OSDI, and CVS symptoms) were analyzed before and at 1 and 2 weeks thereafter.ResultsC3 was a selective and potent TRPM8 agonist without TRPV1 or TRPA1 activity. In test animals, the absence of shaking behavior after C3 perioral administration made it the first choice for further study. C3 increased tear secretion in an animal model of dry eye disease and did not irritate when wiped on eyes of volunteers. C3 singly applied (2 mg/ml) produced significant cooling in <5 min, an effecting lasting 46 min with an increase in tear secretion for 60 min. C3 applied for 2 weeks also significantly increased basal tear secretion with questionnaire surveys of ocular discomfort indices clearly showing improvement of symptoms at 1 and 2 weeks. No complaints of irritation or pain were reported by any subject.ConclusionsC3 is a promising candidate for study of TRPM8 function on the eye surface and for relief of dry eye discomfort.Trial registrationISRCTN24802609 and ISRCTN13359367 . Registered 23 March 2015 and 2 September 2015.

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Identification of a Novel TRPM8 Agonist from Nutmeg: A Promising Cooling Compound.

Publications

Identification of a Novel TRPM8 Agonist from Nutmeg: A Promising Cooling Compound.

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