BCTC

Anti-tumor activity of the TRPM8 inhibitor BCTC in prostate cancer DU145 cells.[Pubmed:26870186]

Oncol Lett. 2016 Jan;11(1):182-188.

The present study investigated the anti-tumor activity of N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox -amide (BCTC), a potent and specific inhibitor of transient receptor potential cation channel subfamily M member 8 (TRPM8) in prostate cancer (PCa) DU145 cells. TRPM8 expression in DU145 and normal prostate PNT1A cells was detected by reverse transcription polymerase chain reaction and western blot analysis. The effect of BCTC on DU145 cells was analyzed by flow cytometry analysis, and MTT, scratch motility and Transwell invasion assays. The molecular mechanism through which BCTC acts was investigated by western blot analysis. TRPM8 expression was increased in DU145 cells compared with PNT1A cells at the mRNA and protein levels. The present study provided evidence that inhibition of TRPM8 by BCTC reduced the viability of DU145 cells, but not PNT1A cells. In addition, BCTC inhibited cell cycle progression, migration and invasion in DU145 cells. Cell cycle-associated proteins, including phosphorylated protein kinase B, cyclin D1, cyclin dependent kinase (CDK) 2 and CDK6 were downregulated by BCTC, while phosphorylated glycogen synthase kinase 3beta was upregulated. However, investigations in the present study revealed that BCTC failed to trigger apoptosis in DU145 cells. In addition, in BCTC-treated DU145 cells, phosphorylated extracellular signal-regulated kinase 1/2 was downregulated substantially while phosphorylated p38 (p-p38) and phosphorylated c-Jun N-terminal kinases (p-JNK) were upregulated. The anti-proliferative activity of BCTC on DU145 cells was attenuated by p38 and JNK-specific inhibitors, suggesting that MAPK pathways are involved. Overall, the TRPM8 specific antagonist BCTC demonstrated excellent anti-tumor activity in PCa DU145 cells, and therefore has the potential to become a targeted therapeutic strategy against PCa.

Effect of transient receptor potential vanilloid 1 (TRPV1) receptor antagonist compounds SB705498, BCTC and AMG9810 in rat models of thermal hyperalgesia measured with an increasing-temperature water bath.[Pubmed:20534382]

Eur J Pharmacol. 2010 Sep 1;641(2-3):135-41.

The transient receptor potential vanilloid 1 (TRPV1) receptor is activated by noxious heat, various endogenous mediators and exogenous irritants. The aim of the present study was to compare three TRPV1 receptor antagonists (SB705498, BCTC and AMG9810) in rat models of heat hyperalgesia. The behavioural noxious heat threshold, defined as the lowest temperature evoking nocifensive reaction, was measured with an increasing-temperature water bath. The effects of TRPV1 receptor antagonists were assessed in thermal hyperalgesia induced by the TRPV1 agonist resiniferatoxin (RTX), mild heat injury (51 degrees C, 20s) or plantar incision in rats. The control heat threshold was 43.2+/-0.4 degrees C. RTX induced an 8-10 degrees C decrease in heat threshold which was dose-dependently inhibited by oral pre-treatment with any of the TRPV1 receptor antagonists with a minimum effective dose of 1mg/kg. The mild heat injury-evoked 7-8 degrees C heat threshold drop was significantly reversed by all three antagonists injected i.p. as post-treatment. The minimum effective doses were as follows: SB705498 10, BCTC 3 and AMG9810 1mg/kg. Plantar incision-induced heat threshold drop (7-8 degrees C) was dose-dependently diminished by an oral post-treatment with any of the antagonists with minimum effective doses of 10, 3 and 3mg/kg, respectively. Assessment of RTX hyperalgesia by measurement of the paw withdrawal latency with a plantar test apparatus yielded 30 mg/kg minimum effective dose for each antagonist. In conclusion, measurement of the noxious heat threshold with the increasing-temperature water bath is suitable to sensitively detect the effects of TRPV1 receptor antagonists in thermal hyperalgesia models.

Use and limitations of three TRPV-1 receptor antagonists on smooth muscles of animals and man: a vote for BCTC.[Pubmed:22056835]

Eur J Pharmacol. 2012 Jan 5;674(1):44-50.

Specificity of the effect is a crucial factor in using antagonists for detecting the physiological/pathophysiological roles of receptors. Here we examined the capsaicin receptor antagonist effects of three commercially-available substances, capsazepine, iodo-resiniferatoxin (I-RTX) and BCTC, on isolated smooth muscle preparations, including the human intestine. Care was taken to observe possible non-specific effects, to find out safe and effective concentrations. Capsazepine appeared to have a low margin of safety. I-RTX (up to 1muM) specifically inhibited capsaicin-induced contractions in the guinea-pig ileum and urinary bladder. I-RTX showed agonist activity on the rat urinary bladder. BCTC (1muM) abolished the contractile effects of capsaicin (1 or 2muM) on all preparations tested (guinea-pig ileum, bladder, trachea, as well as rat and mouse bladder), and on the guinea-pig renal pelvis, where it failed to influence capsaicin-sensitive, sensory neuron-mediated positive inotropy in response to field stimulation. On human intestinal preparations BCTC prevented the relaxant effect of capsaicin. It is concluded that of the three antagonists tested BCTC seems the safest one for inhibiting TRPV-1 receptors. The effect of capsazepine may be complicated by non-specific inhibition of smooth muscle contractility and that of I-RTX by agonist activity. The "local efferent" function of capsaicin-sensitive sensory neurons is not influenced by BCTC, as shown by the results obtained in the renal pelvis. In conclusion, of the TRPV-1 receptor antagonists studied, BCTC (1muM) seems the most reliable in isolated organ experiments. This substance is also effective in the human intestine.

Synthesis of Analogues of BCTC Incorporating a Pyrrolidinyl Linker and Biological Evaluation as Transient Receptor Potential Vanilloid 1 Antagonists.[Pubmed:26360809]

Chem Biol Drug Des. 2016 Feb;87(2):306-11.

A series of novel pyrrolidinyl linker TRPV1 antagonists were prepared in an effort to lower the hyperthermic side-effects of first-generation antagonist BCTC. These compounds were investigated for antagonism of hTRPV1 activation by capsaicin and acid in vitro. Preliminary results suggested the compounds 10a, 10b, 10c and 10j had favorable TRPV1 antagonism activity. In further studies in vivo, 10b, comparable to BCTC, showed potent analgesic activity in capsaicin-induced and heat-induced pain models. In addition, 10b indicated a reduced risk of body temperature elevation. All of these demonstrated that 10b can be considered as a safe candidate for the further development of analgesic drugs.

N-(4-Tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a novel, orally effective vanilloid receptor 1 antagonist with analgesic properties: II. in vivo characterization in rat models of inflammatory and neuropathic pain.[Pubmed:12721336]

J Pharmacol Exp Ther. 2003 Jul;306(1):387-93.

The vanilloid receptor 1 (VR1) is a cation channel expressed predominantly by nociceptive sensory neurons and is activated by a wide array of pain-producing stimuli, including capsaicin, noxious heat, and low pH. Although the behavioral effects of injected capsaicin and the VR1 antagonist capsazepine have indicated a potential role for VR1 in the generation and maintenance of persistent pain states, species differences in the molecular pharmacology of VR1 and a limited number of selective ligands have made VR1 difficult to study in vivo. N-(4-Tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropryazine-1(2H)-carbo x-amide (BCTC) is a recently described inhibitor of capsaicin- and acid-mediated currents at rat VR1. Here, we report the effects of BCTC on acute, inflammatory, and neuropathic pain in rats. Administration of BCTC (30 mg/kg p.o.) significantly reduced both mechanical and thermal hyperalgesia induced by intraplantar injection of 30 micro g of capsaicin. In rats with Freund's complete adjuvantinduced inflammation, BCTC significantly reduced the accompanying thermal and mechanical hyperalgesia (3 mg/kg and 10 mg/kg p.o., respectively). BCTC also reduced mechanical hyperalgesia and tactile allodynia 2 weeks after partial sciatic nerve injury (10 and 30 mg/kg p.o.). BCTC did not affect motor performance on the rotarod after administration of doses up to 50 mg/kg p.o. These data suggest a role for VR1 in persistent and chronic pain arising from inflammation or nerve injury.

N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a novel, orally effective vanilloid receptor 1 antagonist with analgesic properties: I. in vitro characterization and pharmacokinetic properties.[Pubmed:12721338]

J Pharmacol Exp Ther. 2003 Jul;306(1):377-86.

Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the vanilloid receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox -amide (BCTC). Similar to capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC50 value of 6.0 nM), whereas capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by capsazepine. Specificity for VR1 was demonstrated against 63 other receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of approximately 1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than capsazepine for testing the role played by VR1 in rat models of human disease.

BCTC is a potent and specific inhibitor of transient receptor potential cation channel subfamily M member 8 (TRPM8) in prostate cancer (PCa) DU145 cells.

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