We first mentioned Transient Receptor Potential (TRP) Channels/ Receptors in several RxISK posts about withdrawal and they feature on the RxISK Complex Withdrawal Page under Ion Channels. The table on that page gives a fascinating list of herbs and other compounds that could conceivably play a part in stabilizing people who are having withdrawal problems.
Five or more years ago, TRP channels were interesting for 2 reasons. It was clear that many herbs or foodstuffs act on them including herbs and things like Epsom salts, which have been traditional treatments for symptoms like burning feet – common in SSRI dependence and withdrawal.
Another reason was that it seemed like the damage from SSRIs – both PSSD and Dependence and Withdrawal – did not lie in Serotonin Receptors. Was there something that the Serotonin system connects to?
There is. Long before there was any link between serotonin and depression, it was known that antidepressants and lithium and anticonvulsants acted on Ion Channels – especially Sodium channels. These channels control the electrical currents that transmitters like serotonin modulate – they are more basic than serotonin.
In the 1990s and increasingly since there has been interest in a set of what came to be called Transient Receptor Potential channels linked to ion channels.
When devising his serotonin system stabilizing cocktail, as outlined in a recent SSRI Withdrawal post, J began investigating both Ion and TRP Channels. As he says, he/we need a lot more people to chase these as well – both the ones above and those below.
Some of the currently known inhibitors, agonists, antagonists, activators and other compounds currently acting on TRP channels are listed below. This is all new stuff – almost no doctor you meet will know the difference between an agonist and an activator or between an antagonist and an inhibitor.
Don’t be deterred by this. And don’t be worried if chasing compounds on the list below is not for you. It is for Engineers like J. But what RxISK has made clear, is that chasing leads like this is also for women like Heather Roberts and Anne-Marie Kelly who have proven again and again that motivation is worth more than Expertise.
Women motivated to help children or others you know have every chance of unearthing a promising lead by chasing up what can be found about some of the compounds listed below
The list begins simple and fascinating and no work is needed – we start with some well known TRPA agonists but then move on to the compounds we need your help with.
There is no need to start from the top, you might skip to Capsaicin below which is all about pain and numbness or some other compound on the list that jumps off the page at you.
Please leave anything you find in comments below. We will have no other comments on this post other than information about some of these compounds – anything from snippets to detailed leads.
EIPA (L593754) is a TRPP3 channel inhibitor with an IC50 of 10.5 μM. EIPA also inhibits Na+/H+-exchanger (NHE) and macropinocytosis
AC1903 is a specific and selective inhibitor of TRPC5 and has podocyte-protective properties. AC1903 does no effects on TRPC4 or TRPC6 currents and shows no off-target effects in kinase profiling assays. AC1903 suppresses severe proteinuria and prevents podocyte loss in focal segmental glomerulosclerosis (FSGS) rat model.
Amiloride hydrochloride (MK-870 hydrochloride) is an inhibitor of both epithelial sodium channel (ENaC) and urokinase-type plasminogen activeator receptor (uTPA). Amiloride hydrochloride is a blocker of polycystin-2 (PC2; TRPP2) channel.
HC-030031 is a potent and selective TRPA1 inhibitor, which antagonizes AITC- and formalin-evoked calcium influx with IC50s of 6.2±0.2 and 5.3±0.2 μM, respectively.
SKF-96365 hydrochloride is a non-selective TRP Channel blocker.
Pico145 (HC-608) is a remarkable inhibitor of TRPC1/4/5 channels, inhibits (−)-englerin A-activated TRPC4/TRPC5 channels, with IC50s of 0.349 and 1.3 nM in cells, and shows no effect on TRPC3, TRPC6, TRPV1, TRPV4, TRPA1, TRPM2, TRPM8.
Pyr3 is a selective inhibitor of transient receptor potential canonical channel 3 (TRPC3), with an IC50 of 700 nM for TRPC3-mediated Ca2+ influx.
SAR7334 is a potent and specific TRPC6 inhibitor, inhibiting TRPC6 currents with IC50 of 7.9 nM.
N-(p-amylcinnamoyl) Anthranilic Acid (ACA) is a broad spectrum Phospholipase A2 (PLA2) inhibitor and TRP channel blocker. N-(p-amylcinnamoyl) Anthranilic Acid (ACA) is also an effective reversible inhibitor of calcium-activated chloride channels, has potential to treat arrhythmia.
SAR7334 hydrochloride is a potent and specific TRPC6 inhibitor, inhibiting TRPC6 currents with IC50 of 7.9 nM.
BCTC is a potent and specific inhibitor of transient receptor potential cation channel subfamily M member 8 (TRPM8) in prostate cancer (PCa) DU145 cells.
Caffeic acid is an inhibitor of both TRPV1 ion channel and 5-Lipoxygenase (5-LO).
Mifamurtide (MTP-PE; CGP19835) is a drug against osteosarcoma.
Pyr10 is a pyrazole derivative and a selective TRP cation 3 (TRPC3) inhibitor. Pyr10 inhibits Ca2+ influx in carbachol-stimulated TRPC3-transfected HEK293 cells with an IC50 of 0.72 μM (IC50 of 13.08 μM for store operated Ca2+ entry in BRL-2H3 cells). Pyr10 has the ability to distinguish between receptor-operated TRPC3 and native stromal interaction molecule 1 (STIM1)/Orai1 channels.
EIPA hydrochloride (L593754 hydrochloride) is a TRPP3 channel inhibitor with an IC50 of 10.5 μM. EIPA hydrochloride also inhibits Na+/H+- exchanger (NHE) and macropinocytosis.
GSK2798745 is a first-in-class, highly potent, selective, orally active transient receptor potential vanilloid 4 (TRPV4) ion channel blocker with IC50s of 1.8 and 1.6 nM for hTRPV4 and rTRPV4, respectively. GSK2798745 is used in research for the treatment of pulmonary edema associated with congestive heart failure.
Amiloride hydrochloride dihydrate (MK-870 hydrochloride dihydrate) is an inhibitor of both epithelial sodium channel (ENaC) and urokinase-type plasminogen activator receptor (uTPA). Amiloride hydrochloride dihydrate is a blocker of polycystin-2 (PC2; TRPP2) channel.
ML204 hydrochloride is a novel, potent, selective TRPC4 channel inhibitor with IC50 of 0.96 uM.
Resolvin D2 is a metabolite of docosahexaenoic acid (DHA), with anti-inflammatory, anti-infective activities. Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Resolvin D2 is a remarkably potent inhibitor of TRPV1 (IC50 = 0.1 nM) and TRPA1 (IC50 = 2 nM) in primary sensory neurons
Chembridge-5861528 is a TRPA1 channel blocker that antagonizes AITC- and 4-HNE-evoked calcium influx (IC50 values are 14.3 and 18.7μM respectively)
Pyr6 is a selective inhibitor of TRPC3 with IC50 of 0.49 uM(Ca2+ influx inhibition in thapsigargin depleted native RBL-2H3 cells).
Amiloride (MK-870) is an inhibitor of both epithelial sodium channel (ENaC) and urokinase-type plasminogen activator receptor (uTPA). Amiloride is a blocker of polycystin-2 (PC2; TRPP2) channel
GFB-8438 is a potent and subtype selective TRPC5 inhibitor, with IC50s of 0.18 and 0.29 μM of hTRPC5 and hTRPC4, respectively. GFB-8438 shows excellent selectivity against TRPC6, other TRP family members, NaV 1.5, as well as limited activity against the hERG channel. GFB-8438 protects mouse podocytes from injury induced by protamine sulfate.
AP-18 is a potent and selective TRPA1 inhibitor. AP18 blocks activation of TRPA1 by 50 μM Cinnamaldehyde with an IC50 of 3.1 μM and 4.5 μM for human and mouse TRPA1, respectively. AP18 reverses complete Freund’s adjuvant (CFA)-induced mechanical hyperalgesia in mice. AP-18 attenuated 30 μM AITC-induced Yo-Pro uptake in a concentration-dependent manner, with an IC50 of 10.3 μM.
Phenamil methanesulfonate, an analog of Amiloride (HY-B0285), is a more potent and less reversible epithelial sodium channel (ENaC) blocker with an IC50 of 400 nM. Phenamil methanesulfonate is also a competive inhibitor of TRPP3 and inhibits TRPP3-mediated Ca2+ transport with an IC50 of 140 nM in a Ca2+ uptake assay. Phenamil methanesulfonate is an intriguing small molecule to promote bone repair by strongly activating BMP signaling pathway. Phenamil methanesulfonate is used for the research of cystic fibrosis lung disease.
TRPC6-IN-1 is a Transient Receptor Potential Canonical 6 Channel (TRPC6) inhibitor, with an EC50
of 4.66 μM.
Piromelatine (Neu-P11) is a melatonin MT1/MT2 receptor agonist, serotonin 5-HT1A/5-HT1D agonist, and serotonin 5-HT2B antagonist. Piromelatine (Neu-P11) possesses sleep promoting, analgesic, anti-neurodegenerative, anxiolytic and antidepressant potentials. Piromelatine (Neu-P11) also possesses pain-related P2X3, TRPV1, and Nav1.7 channel-inhibition capacities.
CBA is a potent and selective inhibitor of the cation channel TRPM4, with an IC50 of 1.5 μM. CBA can be used for the research of cardiac diseases and prostate cancer.
Capsaicin ((E)-Capsaicin) is a mixture of Capsaicin and Dihydrocapsaicin. Capsaici is a TRPV1 agonist with an EC50 of 0.29 μM in HEK293 cells.
ASP7663 is an orally active and selective TRPA1 agonist. ASP7663 exerts both anti-constipation and anti-abdominal pain actions.
MK6-83 is a new candidate agonist of TRPML1 with an improved efficacy and potency. MK6-83 has the potential for Mucolipidosis type IV study.
Probenecid is a potent and selective agonist of transient receptor potential vanilloid 2 (TRPV2) channels. Probenecid also inhibits pannexin 1 channels.
GSK1016790A is a potent and selective transient receptor potential vanilloid 4 (TRPV4) channel agonist. GSK1016790A can elicit Ca2+ influx and elevate intracellular Ca2+ in HEK cells.
Icilin(AG 3-5) is a synthetic super-agonist of TRPM8 ion channel.
PF-4840154 is a potent, selective agonist of the rat and human TrpA1 channel with EC50s of 97 and 23 nM, respectively. PF-4840154 elicits TrpA1-mediated nocifensive behaviour in mouse.
WS-12 is an agonist of TRPM8 with an EC50 of 39 nM.
Camphor ((±)-Camphor) is a topical anti-infective and anti-pruritic and internally as a stimulant and carminative. However, Camphor is poisonous when ingested. Antiviral, antitussive, and anticancer activities. Camphor is a TRPV3 agonist.
Hydroxy-α-sanshool is an alkylamide isolated from pepper, acts as TRPA1 covalent and TRPV1 non-covalent agonist, with EC50s of 69 and 1.1 µM, respectively.
Imperatorin is an effective of NO synthesis inhibitor (IC50=9.2 μmol), which also is a BChE inhibitor (IC50=31.4 μmol). Imperatorin is a weak agonist of TRPV1 with EC50 of 12.6±3.2 μM.
Nonivamide is a <b<trpv1< b=””>agonist, which exhibits 4d-EC50 value of 5.1 mg/L in static toxicity tests.</b<trpv1<>
JT010 is a potent agonist of TRPA1 with an EC50 of 0.65 nM.
GSK1702934A is a selective TRPC3 agonist. GSK1702934A modulates cardiac contractility and f arrhythmogenesis by activation of TRPC3.
(Z)-Capsaicin is the cis isomer of capsaicin, acts as an orally active TRPV1 agonist, and is used in the research of neuropathic pain.
D-3263 hydrochloride is an enteric-coated, orally bioavailable (transient receptor potential melastatin member 8) TRPM8 agonist.
Podocarpic acid is a natural product, which has the best all-round positive effect and acts as a novel TRPA1 activator.
TRPM8 antagonist WS-3 is an agonist of TRPM8 with an EC50 of 3.7 μM.
Dihydrocapsaicin is a natural capsaicin, acts as a selective TRPV1 agonist, and also increases p-Akt levels. Dihydrocapsaicin enhances the hypothermia-induced neuroprotection.
RN-1747 is a selective transient receptor potential cation channel subfamily V member 4 (TRPV4) agonist, with EC50 values are 0.77 μM, 4.0 μM and 4.1 μM for hTRPV4, mTRPV4 and rTRPV4 respectively. RN-1747 also antagonizes TRPM8, with an IC50 of 4 μM.
MDR-652 is a highly specific and efficacious transient receptor potential vanilloid 1 (TRPV1) ligand with agonist activity. The Kis are 11.4 and 23.8 nM for hTRPV1 and rTRPV1, respectively. The EC50s are 5.05 and 93 nM for hTRPV1 and rTRPV1, respectively. Potent topical analgesic activity.
Capsazepine is a synthetic analogue of the sensory neurone excitotoxin, and an antagonist of TRPV1 receptor with an IC50 of 562 nM.
HC-067047 is a potent and selective TRPV4 antagonist and reversibly inhibits currents through the human, rat, and mouse TRPV4 orthologs with IC50 values of 48 nM, 133 nM, and 17 nM, respectively.
AMG9810 is a selective and competitive vanilloid receptor 1 (TRPV1) antagonist with IC50 values of 24.5 and 85.6 nM for human and rat TRPV1, repectively.
GSK2193874 is an orally active, potent, and selective TRPV4 antagonist with IC50s of 2 nM and 40 nM for rTRPV4 and hTRPV4.
HC-070 is an antagonist of TRPC4/TRPC5, with IC50s of 9.3 nM and 46 nM for hTRPC5 and hTRPC4 in cells, respectively.
AMG 517 is a potent and selective vanilloid receptor-1 (TRPV1) antagonist with an IC50 of 0.5 nM.
BI-749327 is a potent, high selectivity and orally bioavailable TRPC6 antagonist, with IC50s of 13 nM, 19 nM and 15 nM for mouse, human and guinea pig TRPC6, respectively. BI-749327 is 85-fold more selective for mouse TRPC6 than TRPC3 and 42-fold versus TRPC7.
A-967079 is a selective TRPA1 receptor antagonist with IC50s of 67 nM and 289 nM at human and rat TRPA1 receptors, respectively, and has good penetration into the CNS.
RN-1734 is selective antagonist of the TRPV4 channel, completely antagonizes 4αPDD-mediated activation of TRPV4 with comparable, low micromolar IC50s for all three species (hTRPV4: 2.3 μM, mTRPV4: 5.9 μM, rTRPV4: 3.2 μM). RN-1734 clearly decreases the production of tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) without altering the number of olig2-positive cells.
Asivatrep (PAC-14028) is a potent and selective transient receptor potential vanilloid type I (TRPV1) antagonist.
AM-0902 is a potent, selective transient receptor potential A1 (TRPA1) antagonist with IC50s of 71 and 131 nM for rTRPA1 and hTRPA1, respectively.
RQ-00203078 is a highly selective, potent and orally available TRPM8 antagonist (IC50 values are 5.3 and 8.3 nM for rat and human channels respectively), exhibits >350-fold selectivity for TRPM8 over TRPV4, TRPV1 and TRPA1.
SB-366791 is a potent , competitive and selective vanilloid receptor (VR1/TRPV1) antagonist with IC50 of 5.7±1.2 nM target: VR1/TRPV1 IC 50: 5.7±1.2 nM  SB-366791 produced a concentration-dependent inhibition of the response to capsaicin with an apparent pKb of 7.74±0.08.
ML204 is a novel potent antagonist that selectively modulates native TRPC4/C5 ion channels.
GSK205 is a potent, selective TRPV4 antagonist with an IC50 of 4.19 μM for inhibiting TRPV4-mediated Ca2+ influx.
Mavatrep is an orally bioavailable TRPV1 antagonist (Ki=6.5 nM), exhibits minimal effect on the enzymatic activity (IC50 > 25 μM) of CYP isoforms 3A4, 1A2, and 2D6.
(E)-Cardamonin ((E)-Cardamomin) is a novel antagonist of hTRPA1 cation channel with an IC50 of 454 nM.
SB-705498 is a potent, selective and orally bioavailable transient receptor potential vanilloid 1 (TRPV1) receptor antagonist with a pIC50 of 7.1.
JNJ-17203212 is a novel and selective TRPV1 antagonist, with IC50 of 65 nM and 102 nM for human TRPV1 and rat TRPV1.
AMG 333 is a potent and highly selective TRPM8 antagonist with an IC50 of 13 nM.
TRPM8 antagonist 2 is a potent and selective TRPM8 antagonist, with an IC50 of 0.2 nM, used in the research of neuropathic pain syndromes.
ABT-239 is a novel, highly efficacious, non-imidazole class of H3R antagonist and a transient receptor potential vanilloid type 1 (TRPV1) antagonist.
A-1165442 is a potent, competitive and orally available TRPV1 antagonist with an IC50 of 9 nM for human TRPV1.
TC-I 2014 (compound 5) is a potent and orally active Benzimidazole-containing transient receptor potential melastatin 8 (TRPM8) antagonist, with IC50 values of 0.8 nM, 3.0 nM and 4.4 nM for canine, human and rat channels respectively. TC-I 2014 exhibits antiallodynic properties in pain models.
L-R4W2 TFA is a potent antagonist of vanilloid receptor 1 (VR1, TRPV1), with an IC50 of 0.1 μM. L-R4W2 TFA may act as a potent analgesic.
L-R4W2 is a potent antagonist of vanilloid receptor 1 (VR1, TRPV1), with an IC50 of 0.1 μM. L-R4W2 may act as a potent analgesic.
α-Spinasterol, isolated from Spinacia oleracea, has antibacterial activity. α-Spinasterol is a transient receptor potential vanilloid 1 (TRPV1) antagonist, has anti-inflammatory, antidepressant, antioxidant and antinociceptive effects. α-Spinasterol inhibits COX-1 andCOX-2 activities with IC50 values of 16.17 μM and 7.76 μM, respectively.
TRPV antagonist 1 is a transient receptor potential vanilloid (TRPV) antagonist, with an IC50 of < 250 nM.
Diphenyleneiodonium chloride is a NADPH oxidase (NOX) inhibitor and also functions as a TRPA1 activator with an EC50 of 1 to 3 μM. Diphenyleneiodonium chloride selectively inhibits intracellular reactive oxygen species.
2-Aminoethyl diphenylborinate (2-APB) is a cell-permeable inhibitor of IP3R. 2-Aminoethyl diphenylborinate also inhibits the store-operated Ca2+ (SOC) channel and activates some TRP channels (V1, V2 and V3).
(-)-Menthol is a key component of peppermint oil that binds and activates transient receptor potential melastatin 8 (TRPM8), a Ca2+-permeable nonselective cation channel, to increase [Ca2+]i. Antitumor activity.
8-Gingerol, found in the rhizomes of ginger (Z. officinale) with oral bioavailability, activates TRPV1, with an EC50 of 5.0 µM. 8-Gingerol inhibits COX-2, and inhibits the growth of H. pylori in vitro.
Hyperforin dicyclohexylammonium salt (Hyperforin DCHA) is a transient receptor canonical 6 (TRPC6) channels activator. Hyperforin dicyclohexylammonium salt modulates Ca2+ levels by activating Ca2+-conducting non-selective canonical TRPC6 channels. Hyperforin dicyclohexylammonium salt shows antidepressant effect.
SN 2 is a potent activator of TRPML3 ion channel with an EC50 of 1.8 μM. SN 2 also acts as a potent inhibitor of Dengue virus 2 (DENV2) and Zika virus (ZIKV).
Beta-Eudesmol is a natural oxygenated sesquiterpene, activates hTRPA1, with an EC50 of 32.5 μM. Beta-Eudesmol increases appetite through TRPA1.
Linopirdine (DuP 996) is an orally active, selective M-type K+ current (IM; Kv7; KCNQ Channels) inhibitor with an IC50 of 2.4 μM. Linopirdine is a TRPV1 agonist. Linopirdine, a putative cognition enhancing drug, increases acetylcholine release in rat brain tissue.
1,4-Cineole is a widely distributed, natural, oxygenated monoterpene. 1,4-Cineole, present in eucalyptus oil, activates both human TRPM8 and human TRPA1.
Optovin is a reversible photoactive TRPA1 activator; stimulates human TRPA1 channels in vitro and enables repeated photoactivation of motor behaviors in wild-type zebrafish (EC50 = 2 μM).
Adenosine 5′-diphosphoribose sodium (ADP ribose sodium) is a nicotinamide adenine nucleotide (NAD+) metabolite. Adenosine 5′-diphosphoribose sodium is the most potent and primary intracellular Ca2+-permeable cation TRPM2 channel activator. Adenosine 5′-diphosphoribose sodium also can enhance autophagy.
AM12 inhibits Lanthanide-evoked TRPC5 activity with an IC50 of 0.28 μM.
Bisandrographolide C is an unusual dimer of ent-labdane diterpenoid isolated and identified from Andrographis paniculata. Bisandrographolide C activates TRPV1 and TRPV3 channels with Kd values of 289 and 341 μM respectively, and protects cardiomyocytes from hypoxia-reoxygenation injury.
Cyclic ADP-ribose (cADPR) is a potent second messenger for calcium mobilization that is synthesized from NAD+ by a ADP-ribosyl cyclase. Cyclic ADP-ribose increases cytosolic calcium mainly by Ryanodine receptor-mediated release from endoplasmic reticulum and also by extracellular influx through the opening of TRPM2 channels.
Englerin A is a potent and selective activator of TRPC4 and TRPC5 channels, with EC50s of 11.2 and 7.6 nM, respectively. Englerin A can induce renal carcinoma cells death by elevated Ca2+ influx and Ca2+ cell overload.
Pulegone, the major chemical constituent of Calamintha nepeta (L.) Savi essential oil which is an aromatic herb with a mint-oregano flavor, is one of avian repellents. The molecular target for the repellent action of Pulegone in avian species is nociceptive TRP ankyrin 1 (TRPA1). Pulegone stimulates both TRPM8 and TRPA1 channel in chicken sensory neurons and suppresses the former but not the latter at high concentrations.
Umbellulone is an active constituent of the leaves of Umbellularia californica. Umbellulone stimulates the TRPA1 channel in a subset of peptidergic, nociceptive neurons, activating the trigeminovascular system via this mechanism.
Methyl syringate, a chemical marker of asphodel monofloral honey, is an efficient phenolic mediator for bacterial and fungal laccases. Methyl syringate is a TRPA1 agonist.
Rosiglitazone (BRL 49653) is a selective, orally active PPARγ agonist with EC50s of 30 nM, 100 nM and 60 nM for PPARγ1, PPARγ2, and PPARγ, respectively. Rosiglitazone binds to PPARγ with a Kd of approximately 40 nM. Rosiglitazone is also an activator of TRPC5 (EC50=~30 μM) and an inhibitor of TRPM3
Rosiglitazone maleate (BRL 49653C) is a potent and selective activator of PPARγ, with EC50s of 30 nM, 100 nM and 60 nM for PPARγ1, PPARγ2, and PPARγ, respectively, and a Kd of appr 40 nM for PPARγ; Rosiglitazone maleate is also an modulator of TRP channels, inhibits TRP melastatin 2 (TRPM2), TRPM3 and activates TRP canonical 5 (TRPC5).