Capsaicin and its analogues: Structure-activity relationship study

Current Medicinal Chemistry

Volumn 20, Issue 21, 2013, Pages 2661-2672

  Huang, X F ^a,b   Xue, J Y ^a,b   Jiang, A Q ^a   Zhu, H L ^a  

^a NANJING UNIVERSITY   (China)

^b CHANGZHOU UNIVERSITY   (China)

Author keywords

Analgesic; Anti cancer; Capsaicin; Gastroprotection; Structure and activity relationship; Vasorelaxation

Indexed keywords

1,1 DIPHENYL 2 PICRYLHYDRAZYL; ANALGESIC AGENT; ANTIINFLAMMATORY AGENT; ANTINEOPLASTIC AGENT; ANTIOXIDANT; CAPSAICIN; CAPSAICIN DERIVATIVE; NITRIC OXIDE; RESINIFERATOXIN; SUBSTANCE P; VANILLOID RECEPTOR 1; VASODILATOR AGENT;

ABDOMINAL PAIN; ANALGESIA; ANTIINFLAMMATORY ACTIVITY; ANTINEOPLASTIC ACTIVITY; ANTINOCICEPTION; ANTIOXIDANT ACTIVITY; ANTIPROLIFERATIVE ACTIVITY; APOPTOSIS; ARTICLE; BINDING SITE; BRONCHOSPASM; BURNING SENSATION; CELL CYCLE ARREST; COUGHING; DESENSITIZATION; DIARRHEA; DNA FRAGMENTATION; DRUG MECHANISM; DRUG PROTEIN BINDING; DRUG STRUCTURE; GUINEA PIG; HUMAN; INNATE IMMUNITY; IODINATION; LIPID PEROXIDATION; MOLECULAR BIOLOGY; NAUSEA; NEUROPATHIC PAIN; NONHUMAN; PROTEIN EXPRESSION; PRURITUS; SENSORY NERVE CELL; SKIN CARCINOGENESIS; STOMACH PROTECTION; STRUCTURE ACTIVITY RELATION; VASODILATATION; VOMITING;

ANALGESICS; ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; ANTINEOPLASTIC AGENTS, PHYTOGENIC; CAPSAICIN; CELL PROLIFERATION; HUMANS; MOLECULAR STRUCTURE; NEOPLASMS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84880283965     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/0929867311320210004     Document Type: Article

References (110)

1. Sawynok, J. Topical analgesics in neuropathic pain. Curr. Pharm. Des., 2005, 11, 2995-3004.
2. Kosuge, S.; Furuta, M. Study on pungent principle of Capsicum part X IV. chemical constitution of the pungent principle. Agric. Boil. Chem., 1970, 34, 248-256.
3. Gunthorpe, M.J.; Szallasi, A. Peripheral TRPV1 receptors as targets for drug development: New molecules and mechanisms. Curr. Pharm. Des., 2008, 14, 32-41.
4. Suri, A.; Szallasi, A. The emerging role of TRPV1 in diabetes and obesity. Trends Pharmacol. Sci., 2008, 29, 29-36.
5. Sterner, O.; Szallasi, A. Novel natural vanilloid receptor agonists: New therapeutic targets for drug development. Trends Pharmacol. Sci., 1999, 20, 459-465.
6. Surh, Y. Molecular mechanisms of chemopreventive effects of selected dietary and medicinal phenolic substances. Mutat. Res., 1999, 428, 305-327.
7. Tominaga, M.; Tominaga, T. Structure and function of TRPV1. Pflug. Arch., 2005, 451, 143-150.
8. Caterina, M.J.; Julius, D. The vanilloid receptor: A molecular gateway to the pain pathway. Annu. Rev. Neurosci., 2001, 24, 487-517.
9. Caterina, M.J.; Schumacher, M.A.; Tominaga, M.; Rosen, T.A.; Levine, J.D.; Julius, D. The capsaicin receptor: A heat-activated ion channel in the pain pathway. Nature, 1997, 389, 816-824.
10. Gamse, R.; Lackner, D.; Gamse, G.; Leeman, S.E. Effect of capsaicin pretreatment on capsaicin-evoked release of immunoreactive somatostatin and substance P from primary sensory neurons. Naunyn-Schmiedebergs Arch. Pharmacol., 1981, 316, 38-41.
11. Gamse, R.; Holzer, P.; Lembeck, F. Decrease of substance P in primary afferent neurones and impairment of neurogenic plasma extravasation by capsaicin. Br. J. Pharmacol., 1980, 68, 207-213.
12. Khalil, Z.; Helme, R. Sensory peptides as neuromodulators of wound healing in aged rats. J. Gerontol. A. Biol. Sci. Med. Sci., 1996, 51, B354-361.
13. Hayman, Mark.; Kam, P.C.A. Capsaicin: A review of its pharmacology and clinical applications. Curr. Anaesth. Crit. Care, 2008, 19, 338-343.
14. Cortright, D.N.; Szallasi, A. Biochemical pharmacology of the vanilloid receptor TRPV1. An update. Eur. J. Biochem., 2004, 271, 1814-1819.
15. Liu, L.; Simon, S.A. Modulation of IA currents by capsaicin in rat trigeminal ganglion neurons. J. Neurophysiology, 2003, 89, 1387-1401.
16. Kárai, L.J.; Russell, J.T.; Iadarola, M.J.; Oláh, Z. Vanilloid receptor 1 regulates multiple calcium compartments and contributes to Ca2+-induced Ca2+ release in sensory neurons. J. Biol. Chem., 2004, 16, 16377-16387.
17. Baamonde, A.; Lastra, A.; Juarez, L.; Hidalgo, A.; Menéndez, L. TRPV1 desensitisation and endogenous vanilloid involvement in the enhanced analgesia induced by capsaicin in inflamed tissues. Brain Res. Bull., 2005, 30, 476-481.
18. Ahern, G.P.; Brooks, I.M.; Miyares, R.L.; Wang, X.B. Extracellular cations sensitize and gate capsaicin receptor TRPV1 modulating pain signaling. J. Neurosci., 2005, 25, 5109-5116.
19. Wu, Z.Z.; Chen, S.R.; Pan, H.L. Transient receptor potential vanilloid type 1 activation down-regulates voltage-gated calcium channels through calcium-dependent calcineurin in sensory neurons. J. Biol. Chem., 2005, 280, 18142-18151.
20. Koplas, P.A.; Rosenberg, R.L.; Oxford, G.S. The role of calcium in the desensitization of capsaicin responses in rat dorsal root ganglion neurons. J. Neuroscience, 1997, 17, 3525-3537.
21. Liu, L.; Simon, S.A. Capsaicin-induced currents with distinct desensitization and Ca2+ dependence in rat trigeminal ganglion cells. J. Neurophysiology, 1996, 75, 1503-1514.
22. Mohapatra, D.P.; Nau, C. Regulation of Ca2+-dependent desensitization in the vanilloid receptor TRPV1 by calcineurin and cAMPdependent protein kinase. J. Biol. Chem., 2005, 280, 13424-13432.
23. Ruparel, N.B.; Patwardhan, A.M.; Akopian, A.N.; Hargreaves, K.M. Homologous and heterologous desensitization of capsaicin and mustard oil responses utilize different cellular pathways in nociceptors. Pain, 2008, 135, 271-279.
24. Vyklicky, L.; Novakova-Tousova, K.; Benedikt, J.; Samad, A.; Touska, F.; Vlachova, V. Calcium-dependent desensitization of vanilloid receptor TRPV1: A mechanism possibly involved in analgesia induced by topical application of capsaicin. Physiol. Res., 2008, 57, S59-S68.
25. Kuenzi, F.M.; Dale, N. Effect of capsaicin and analogues on potassium and calcium currents and vanilloid receptors in Xenopus embryo spinal neurones. Br. J. PharmacoL., 1996, 119, 81-89.
26. Aranda, R.J.; Villalain, J.; Gomez-Fernandez, J.C. Capsaicin affects the structure and phase organization of phospholipid membranes. Biochim. Biophys. Acta., 1995, 1234, 225-234.
27. Feigin, A.M.; Aronov, E.V.; Bryant, B.P.; Teeter, J.H.; Brand, J.G. Capsaicin and its analogs induce ion channels in planar lipid bilayers. Neuroreport, 1995, 6, 2134-2136.
28. Cochereau, C.; Sanchez, D.; Bourhaoui, A.; Creppy, E.E. Capsaicin, a structural analog of tyrosine, inhibits the aminoacylation of tRNA(Tyr). Toxicol. Appl. Pharmacol., 1996, 141, 133-137.
29. Xu, Y.P.; Zhang, J.W.; Li, L.; Ye, Z.Y.; Zhang, Y.; Gao, X.; Li, F.; Yan, X.S.; Liu, Z.G.; Liu, L.J.; Cao, X.H. Complex regulation of capsaicin on intracellular second messengers by calcium dependent and independent mechanisms in primary sensory neurons. Neurosci. Lett., 2012, 517, 30-35.
30. Mason, L.; Moore, R.A.; Derry, S.; Edwards, J.E.; McQuay, H.J. Systematic review of topical capsaicin for the treatment of chronic pain. BMJ, 2004, 328, 991.
31. Hempenstall, K.; Nurmikko, T.J.; Johnson, R.W.; A'Hern, R.P.; Rice, A.S. Analgesic therapy in postherpetic neuralgia: A quantitative systematic review. PLoS Med., 2005, 2, e164.
32. Paice, J.A.; Ferrans, C.E.; Lashley, F.R.; Shott, S.; Vizgirda, V.; Pitrak, D. Topical capsaicin in the management of HIV-associated peripheral neuropathy. J. Pain Symptom Manage., 2000, 19, 45-52.
33. Peppin, J.F.; Majors, K.; Webster, L.R.; Simpson, D.M.; Tobias, J.K.; Vanhove, G.F. Tolerability of NGX-4010, a capsaicin 8% patch for peripheral neuropathic pain. J. Pain Res., 2011, 4, 385-392.
34. Webster, L.R.; Peppin, J.F.; Murphy, F.T.; Lu, B.; Tobias, J.K.; Vanhove, G.F. Efficacy, safety, and tolerability of NGX-4010, capsaicin 8% patch, in an open-label study of patients with peripheral neuropathic pain. Diabetes Res. Clin. Pract., 2011, 93, 187-197.
35. Webster, L.R.; Nunez, M.; Tark, M.D.; Dunteman, E.D.; Lu, B.; Tobias, J.K.; Vanhove, G.F. Tolerability of NGX-4010, a capsaicin 8% dermal patch, following pretreatment with lidocaine 2.5%/prilocaine 2.5% cream in patients with post-herpetic neuralgia. BMC Anesthesiology, 2011, 11, 25.
36. Park, K.K.; Surh, Y.J. Effects of capsaicin on chemically-induced two-stage mouse skin carcinogenesis. Cancer Lett., 1997, 114, 183-184.
37. Yoshitani, S.I.; Tanaka, T.; Kohno, H.; Takashima, S. Chemoprevention of azoxymethane-induced rat colon carcinogenesis by dietary capsaicin and rotenone. Int. J. Oncol., 2001, 19, 929-939.
38. Anandakumar, P.; Jagan, S.; Kamaraj, S.; Ramakrishnan, G.; Titto, A.A.; Devaki, T. Beneficial influence of capsaicin on lipid peroxidation, membrane-bound enzymes and glycoprotein profile during experimental lung carcinogenesis. J. Pharm. Pharmacol., 2008, 60, 803-808.
39. Tanaka, T.; Kohno, H.; Sakata, K.; Yamada, Y. ; Hirose, Y.; Sugie, S.; Mori, H. Modifying effects of dietary capsaicin and rotenone on 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis. Carcinogenesis, 2002, 23, 1361-1367.
40. Mori A, Lehmann S, O'Kelly J, Kumagai T, Desmond JC, Pervan M, McBride, W.H.; Kizaki, M.; Koeffler, H.P. Capsaicin, a component of red peppers, inhibits the growth of androgenindependent, p53 mutant prostate cancer cells. Cancer Res., 2006, 66, 3222-3229.
41. Sanchez, A.M.; Malagarie-Cazenave, S.; Olea, N.; Vara, D.; Chiloeches, A.; Diaz-Laviada, I. Apoptosis induced by capsaicin in prostate PC-3 cells involves ceramide accumulation, neutral sphingomyelinase, and JNK activation. Apoptosis, 2007, 12, 2013-2024.
42. Malagarie-Cazenave, S.; Olea-Herrero, N.; Vara, D.; Morell, C.; Díaz-Laviada, I. The vanilloid capsaicin induces IL-6 secretion in prostate PC-3 cancer cells. Cytokine, 2011, 54, 330-337.
43. Oyagbemi, A.A.; Saba, A.B.; Azeez, O.I. Capsaicin: A novel chemopreventive molecule and its underlying molecular mechanisms of action. Indian J. Cancer, 2010, 47, 53-58.
44. Sanchez, M.G.; Sanchez, A.M.; Collado, B.; Malagarie-Cazenave, S.; Olea, N.; Carmena, M.J.; Prieto, J.; Diaz-Laviada I. Expression of the transient receptor potential vanilloid 1 (TRPV1) in LNCaP and PC-3 prostate cancer cells and in human prostate tissue. Eur. J. Pharmacol., 2005, 515, 20-27.
45. Athanasiou, A.; Smith, P.A.; Vakilpour, S.; Kumaran, N.M.; Turner, A.E.; Bagiokou, D.; Layfield, R.; Ray, D.E.; Westwell, A.D.; Alexander, S.P.; Kendall, D.A.; Lobo, D.N.; Watson, S.A.; Lophatanon, A.; Muir, K.A.; Guo, D.A.; Bates, T.E. Vanilloid receptor agonists and antagonists are mitochondrial inhibitors: How vanilloids cause non-vanilloid receptor mediated cell death. Biochem. Biophys. Res. Commun., 2007, 354, 50-55.
46. Ghosh, A.K.; Basu, S. Fas-associated factor 1 is a negative regulator in capsaicin induced cancer cell apoptosis. Cancer Letters, 2010, 287, 142-149.
47. Zizan, A.A.; Blevins, R.D. Mutagenicity and antimutagenicity testing of six chemicals associated with the pungent properties of specific species as revealed by the Ames Salmonella/microsomal assay. Arch. Environ. Contam. Toxicol., 1995, 28, 248-258.
48. Agrawal, R.C.; Wiessler, M.; Hecker, E.; Bhide, S.V. Tumourpromoting effect of chilli extract in BALB/c mice. Int. J. Cancer, 1986, 38, 689-695.
49. Matucci-Cerinic, M.; Marabini, S.; Jantsch, S.; Cagnoni, M.; Partsch, G. Effects of capsaicin on the metabolism of rheumatoid arthritis synoviocytes in vitro. Ann. Rheum. Dis., 1990, 49, 598-602.
50. Verschoyle, R.D.; Steward, W.P.; Gescher, A.J. Putative cancer chemopreventive agents of dietary origin-how safe are they? Nutr. Cancer, 2007, 59, 152-162.
51. Surh, Y.J.; Lee, S.S. Capsaicin in hot chili pepper: Carcinogen, cocarcinogen or anticarcinogen? Food Chem. Toxicol., 1996, 34, 313-316.
52. Serra I, Yamamoto M, Calvo A, Cavada G, Báez S, Endoh K, Watanabe, H.; Tajima, K. Association of chili pepper consumption, low socioeconomic status and longstanding gallstones with gallbladder cancer in a Chilean population. Int. J. Cancer, 2002, 102, 407-411.
53. López-Carrillo, L.; Hernández, A.M.; Dubrow, R. Chili pepper consumption and gastric cancer in Mexico: A case-control study. Am. J. Epidemiol., 1994, 139, 263-271.
54. Bode, A.M.; Dong, Z. The two faces of capsaicin. Cancer Res., 2011, 71, 2809-2814.
55. Franco-Cereceda, A.; Rudehill, A. Capsaicin-induced vasodilatation of human coronary-arteries in vitro is mediated by calcitonin gene-related peptide rather than substance-P or neurokinin-A. Acta Physiol. Scand., 1989, 136, 575-580.
56. Franco-Cereceda, A.; Rudehill, A.; Lundberg, J.M. Calcitonin gene-related peptide but not substance-P mimics capsaicin-induced coronary vasodilation in the pig. Eur. J. Pharmacol., 1987, 142, 235-243.
57. Jansen, I.; Alafaci, C.; Uddman, R.; Edvinsson, L. Evidence that calcitonin generelated peptide contributes to the capsaicin-induced relaxation of guinea-pig cerebral-arteries. Regul. Pept., 1990, 31, 167-178.
58. Zygmunt, P.M.; Petersson, J.; Andersson, D.A.; Chuang, H.H.; Sorgard, M.; Di Marzo, V.; Julius, D.; Hogestatt, E.D. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature, 1999, 400, 452-457.
59. Hwang, S.W.; Cho, H.; Kwak, J.; Lee, S.Y.; Kang, C.J.; Jung, J.; Cho, S.; Min, K.H.; Suh, Y.G.; Kim, D.; Oh, U. Direct activation of capsaicin receptors by products of lipoxygenases: Endogenous capsaicin-like substances. Proc. Natl. Acad. Sci. U.S.A., 2000, 97, 6155-6160.
60. Dunn, W.R.; Hardy, T.A.; Brock, J.A. Electrophysiological effects of activating the peptidergic primary afferent innervation of rat mesenteric arteries. Br. J. Pharmacol., 2003, 140, 231-238.
61. Akerman, S.; Kaube, H.; Goadsby, P.J. Vanilloid type 1 receptors (VR1) on trigeminal sensory nerve fibres play a minor role in neurogenic dural vasodilatation, and are involved in capsaicin-induced dural dilation. Br. J. Pharmacol., 2003, 140, 718-724.
62. Gupta, S.; Akerman, S.; van den Maagdenberg, A.M.J.M.; Saxena, P.R.; Goadsby, P.J.; van den Brink, A.M. Intravital microscopy on a closed cranial window in mice: A model to study trigeminovascular mechanisms involved in migraine. Cephalalgia, 2006, 26, 1294-1303.
63. Lo, Y.C.; Wu, S.N.; Wu, J.R.; Chen, I.J. Effect of capsaicin onmembrane currents in cultured vascular smooth muscle cells of rat aorta. Eur. J. Pharmacol., 1995, 392, 321-328.
64. Hopps, J.J.; Dunn, W.R.; Randall, M.D. Vasorelaxation to capsaicin and its effects on calcium influx in arteries. Eur. J. Pharmacol., 2012, 681, 88-93.
65. Ellis, J.L.; Sham, J.S.K.; Undem, B.J. Tachykinin-independent effects of capsaicin on smooth muscle in human isolated bronchi. Am. J. Respir. Crit. Care Med., 1997, 155, 751-755.
66. Mitchell, J.A.; Williams, F.M.; Williams, T.J.; Larkin, S.W. Role of nitric oxide in the dilator actions of capsaicin-sensitive nerves in the rabbit coronary circulation. Neuropeptides, 1997, 31, 333-338.
67. Van Crombruggen, K.; Van Nassauw, L.; Derycke, L.; Timmermans, J.P.; Holtappels, G.; Hall, D.; Bachert, C. Capsaicin-induced vasodilatation in human nasal vasculature is mediated by modulation of cyclooxygenase-2 activity and abrogated by sulprostone. Naunyn Schmiedebergs Arch. Pharmacol., 2011, 383, 613-626.
68. Calignano, A.; Katona, I.; Desarnaud, F.; Giuffrida, A.; La Rana, G.; Mackie, K.; Freund, T.F.; Piomelli, D. Bidirectional control of airway responsiveness by endogenous cannabinoids. Nature, 2000, 408, 96-101.
69. Fujimoto, S.; Mori, M.; Tsushima, H.; Kunimatsu, M. Capsaicininduced, capsazepineinsensitive relaxation of the guinea-pig ileum. Eur. J. Pharmacol., 2006, 530, 144-151.
70. Sheykhzade, M.; Gupta, S.; Sørensen, T.; Sørensen, O.A.; Koch, H.; Boonen, H.C.; Back, O.; Fjalland, B. Characterization of capsaicin induced responses in mice vas deferens: Evidence of CGRP uptake. Eur. J. Pharmacol., 2011, 667, 375-382.
71. Patane, S. ; Marte, F.; La Rosa, F.C.; La Rocca, R. Capsaicin and arterial hypertensive crisis. Int. J. Cardiol., 2010, 144, e26-27.
72. Dutta, A.; Deshpande, SB. Mechanisms underlying the hypertensive response induced by capsaicin. Int. J. Cardiol., 2010, 145, 358-359.
73. Holzer, P.; Peskar, B.M.; Peskar, B.A.; Amann, R. Release of calcitonin gene-related peptide induced by capsaicin in the vascularly perfused rat stomach. Neurosci. Lett., 1990, 108, 195-200.
74. Sternini, C.; Reeve, J.R.; Brecha, N. Distribution and characterization of calcitonin gene-related peptide immunoreactivity in the digestive system of normal and capsaicin-treated rats. Gastroenterology, 1987, 93, 852-862.
75. Ren, J.; Young, R.L.; Lassiter, D.C.; Harty, R.F. Calcitonin generelated peptide mediates capsaicin-induced neuroendocrine responses in rat antrum. Gastroenterology, 1993, 104, 485-491.
76. Wimalawansa, S.J. The effects of neonatal capsaicin on plasma levels and tissue contents of CGRP. Peptides, 1993, 14, 247-252.
77. Abdel-Salam, O.M.; Szolcsányi, J.; Mózsik, G. Capsaicin and the stomach. A review of experimental and clinical data. J. Physiol. Paris., 1997, 91, 151-171.
78. Mózsik, G.; Szolcsányi, J.; Rácz, I. Gastroprotection induced by capsaicin in healthy human subjects. World J. Gastroenterol., 2005, 11, 5180-5184.
79. Brown, D.C.; Iadarola, M.J.; Perkowski, S.Z.; Erin, H.; Shofer, F.; Laszlo, K.J.; Olah, Z.; Mannes, A.J. Physiologic and antinociceptive effects of intrathecal resiniferatoxin in a canine bone cancer model. Anesthesiology, 2005, 103, 1052-1059.
80. Bodó, E.; Bíró, T.; Telek, A.; Czifra, G.; Griger, Z.; Tóth, B.I. Mescalchin, A.; Ito, T.; Bettermann, A.; Kovács, L.; Paus, R. A hot new twist to hair biology: Involvement of vanilloid receptor-1 (VR1/TRPV1) signaling in human hair growth control. Am. J. Pathol., 2005, 166, 985-998.
81. Zhang, L.L.; Liu, D.Y.; Ma, L.Q.; Luo, Z.D.; Cao, T.B.; Zhong, J.; Yan, Z.C.; Wang, L.J.; Zhao, Z.G.; Zhu, S.J.; Schrader, M.; Thilo, F.; Zhu, Z.M.; Tepel, M. Activation of transient receptor potential vanilloid type-1 (TRPV1) channel prevents adipogenesis and obesity. Circ Res., 2007, 100, 1063-1070.
82. Henderson, D.E.; Slickman, A.M.; Henderson, S.K. Quantitative HPLC determination of the antioxidant activity of capsaicin on the formation of lipid hydroperoxides of linoleic acid: A comparative study against BHT and melatonin. J. Agric. Food Chem., 1999, 47, 2563-2570.
83. Asai, A.; Nakagawa, K.; Miyazawa, T. Antioxidative effects of turmeric, rosemary and capsicum extracts on membrane phospholipid peroxidation and liver lipid metabolism in mice. Biosci. Biotechnol. Biochem., 1999, 63, 2118-2122.
84. Kogure, K.; Goto, S.; Nishimura, M.; Yasumoto, M.; Abe, K.; Ohiwa, C.; Sassa, H.; Kusumi, T.; Terada, H. Mechanism of potent antiperoxidative effect of capsaicin. Biochimica et Biophysica Acta, 2002, 1573, 84-92.
85. Gertsch, J.; Guttinger, M.; Sticher, O.; Heilmann, J. Relative quantification of mRNA levels in Jurkat T cells with RT-real time-PCR (RT-rt-PCR): New possibilities for the screening of antiinflammatory and cytotoxic compounds. Pharm. Res., 2002, 19, 1236-1243.
86. Mahmoud, M.E.; Nikami, H.; Shiina, T.; Takewaki, T.; Shimizu, Y. Capsaicin inhibits IFN-k-induced MHC class II expression by suppressing transcription of class II transactivator gene in murine peritoneal macrophages. Int. Immunopharmacol., 2010, 10, 86-90.
87. Kim, C.S.; Kawada, T.; Kim, B.S.; Han, I.S.; Choe, S.Y.; Kurata, T.; Yu, R. Capsaicin exhibits anti-inflammatory property by inhibiting IkB-A degradation in LPS-stimulated peritoneal macrophages. Cell Signal, 2003, 15, 299-306.
88. Chen, C.W.; Lee, S.T.; Wu, W.T.; Fu, W.M.; Ho, F.M.; Lin, W.W. Signal transduction for inhibition of inducible nitric oxide synthase and cyclooxygenase-2 induction by capsaicin and related analogs in macrophages. Br. J. Pharmacol., 2003, 140, 1077-1087.
89. Kobata, K.; Todo, T.; Yazawa, S.; Iwai, K.; Watanabe, T. Novel capsaicinoid-like substances, capsiate and dihydrocapsiate, from the fruits of a nonpungent cultivar, CH-19 Sweet, of pepper (Capsicum annuum L.). J. Agric. Food Chem., 1998, 46, 1695-1697.
90. Jordt, S.E.; Julius, D. Molecular basis for species-specific sensitivity to "hot" chili peppers. Cell, 2002, 108, 421-430.
91. Walpole, C.S.J.; Wrigglesworth, R.; Bevan, S.; Campbell, E.A.; Dray, A.; James, I.F.; Perkins, M.N.; Reid, D.J.; Winter, J. Analogues of capsaicin with agonist activity as novel analgesic agents; structure-activity studies. 1. the aromatic "A-region". J. Med. Chem., 1993, 36, 2362-2372.
92. Rosa, A.; Appendino, G.; Melis, M.P.; Deiana, M.; Atzeri, A.; Alessandra, I.; Minassi, A.; Dessì, M.A. Protective effect and relation structure-activity of nonivamide and iododerivatives in several models of lipid oxidation. Chemico-Biological Interactions, 2009, 180, 183-192.
93. Sivakumar, R.; Divakar, S. Syntheses of N-vanillyl-nonanamide glycosides using amyloglucosidase from Rhizopus and ?-glucosidase from sweet almond. Biotechnol. Lett., 2007, 29, 1537-1548.
94. Shimoda, K.; Kwon, S.; Utsuki, A.; Ohiwa, S.; Katsuragi, H.; Yonemoto, N.; Hamada, H.; Hamada, H. Glycosylation of capsaicin and 8-nordihydrocapsaicin by cultured cells of Catharanthus roseus. Phytochemistry, 2007, 68, 1391-1396.
95. Ochi, T.; Takaishi, Y.; Kogure, K.; Yamauti, I. Antioxidant activity of a new capsaicin derivative from Capsicum annuum. J. Nat. Prod., 2003, 66, 1094-1096.
96. Thomas, K.C.; Ethirajan, M.; Shahrokh, K.; Sun, H.; Lee, J.; Cheatham III, T.E.; Yost, G.S.; Reilly, C.A. Structure-activity relationship of capsaicin analogs and transient receptor potential vanilloid 1-mediated human lung epithelial cell toxicity. J. Pharm. Exp. Ther., 2011, 337, 400-410.
97. Iida, T.; Moriyama, T.; Kobata, K.; Morita, A.; Murayama, N.; Hashizume, S.; Fushiki, T.; Yazawa, S.; Watanabe, T.; Tominaga, M. TRPV1 activation and induction of nociceptive response by a non-pungent capsaicin-like compound, capsiate. Neuropharmacology, 2003, 44, 958-967.
98. He, G.J.; Ye, X.L.; Mou, X.; Chen, Z.; Li, X.G. Synthesis and antinociceptive activity of capsinoid derivatives. Eur. J. Med. Chem., 2009, 44, 3345-3349.
99. Walpole, C.S.J.; Wrigglesworth, R.; Bevan, S.; Campbell, E.A.; Dray, A.; James, I.F.; Masdin, K.J.; Perkins, M.N.; Winter, J. Analogues of capsaicin with agonist activity as novel analgesic agents; structure-activity studies. 2. the amide bond "B-region". J. Med. Chem., 1993, 36, 2373-2380.
100. Walpole, C.S.J.; Bevan, S.; Bovermann, G.; Boelsterli, J.J.; Breckenridge, R.; Davies, J.W.; Hughes, G.A.; James, I.; Oberer, L.; Winter, J.; Wrigglesworth, R. The discovery of capsazepine, the first competitive antagonist of the sensory neuron excitants capsaicin and resiniferatoxin. J. Med. Chem., 1994, 37, 1942-1954.
101. Walpole, C.S.J.; Wrigglesworth, R.; Bevan, S.; Campbell, E.A.; Dray, A.; James, I.F.; Masdin, K.J.; Perkins, M.N.; Winter, J. Analogues of capsaicin with agonist activity as novel analgesic agents; structure-activity studies. 3. the hydrophobic side-chain "Cregion". J. Med. Chem., 1993, 36, 2381-2389.
102. Janusz, J.M.; Buckwalter, B.L.; Young, P.A.; LaHann, T.R.; Farmer, R.W.; Kasting, G.B.; Loomans, M.E.; Kerckaert, G.A.; Maddin, C.S.; Berman, E.F.; Bohne, R.L.; Cupps, T.L.; Milstein, J.R. Vanilloids. 1. Analogs of capsaicin with antinociceptive and antiinflammatory activity. J. Med. Chem., 1993, 36, 2595-2604.
103. Tuoya; Baba, N.; Shimoishi, Y.; Murata, Y.; Tada, M.; Koseki, M.; Takahata, K. Apoptosis induction by dohevanil, a DHA substitutive analog of capsaicin, in MCF-7 cells. Life Sciences, 2006, 78, 1515-1519.
104. Wrigglesworth, R.; Walpole, C.S.J.; Bevan, S.; Campbell, E.A.; Dray, A.; Hughes, G.A.; James, I.; Masdin, K.J.; Winter, J. Analogues of capsaicin with agonist activity as novel analgesic agents: Structure-activity Studies. 4. potent, orally active analgesics. J. Med. Chem., 1996, 39, 4942-4951.
105. Urban, L.; Campbell, E.A.; Panesar, M.; Patel, S.; Chaudhry, N.; Kane, S.; Buchheit, K.H.; Sandells, B.; James, I.F. In vivo pharmacology of SDZ 249-665, a novel, non-pungent capsaicin analogue. Pain, 2000, 89, 65-74.
106. Szallasi, A.; Blumberg, P.M.; Annicelli, L.L.; Krause, J.E.; Cortright, D.N. The cloned rat vanilloid receptor VR1 mediates both R-type binding and C-type calcium response in dorsal root ganglion neurons. Mol. Pharmacol., 1999, 56, 581-587.
107. Lee, J.; Lee, J.; Kim, J.; Kim, S.Y.; Chun, M.W.; Cho, H.; Hwang, S.W.; Oh, U.; Park, Y.H.; Marquez, V.E.; Beheshti, M.; Szabo, T.; Blumberg, P.M. N-(3-Acyloxy-2-benzylpropyl)-N'-(4-hydroxy-3-methoxybenzyl) thiourea derivatives as potent vanilloid receptor agonists and analgesics. Bioorg. Med. Chem., 2001, 9, 19-32.
108. Lee, J.; Lee, J.; Kang, M.; Shin, M.; Kim, J.M.; Kang, S.U.; Lim, J.O.; Choi, H.K.; Suh, Y.G.; Park, H.G.; Oh, U.; Kim, H.D.; Park, Y.H.; Ha, H.J.; Kim, Y.H.; Toth, A.; Wang, Y.; Tran, R.; Pearce, L.V.; Lundberg, D.J.; Blumberg, P.M. N-(3-Acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues: Novel potent and high affinity antagonists and partial antagonists of the vanilloid receptor. J. Med. Chem., 2003, 46, 3116-3126.
109. Chung, J.U.; Kim, S.Y.; Lim, J.O.; Choi, H.K.; Kang, S.U.; Yoon, H.S.; Ryu, H.C.; Kang, D.W.; Lee, J.; Kang, B.; Choi, S.; Toth, A.; Pearce, L.V.; Pavlyukovets, V.A.; Lundbergc, D.J.; Blumberg, P.M. α-Substituted N-(4-tert-butylbenzyl)-N'-[4-(-methylsulfonylamino)-benzyl]thiourea analogues as potent and stereospecific TRPV1 antagonists. Bioorg. Med. Chem., 2007, 15, 6043-6053.
110. Ryu, H.C.; Jin, M.K.; Kim, S.Y.; Choi, H.K.; Kang, S.U.; Kang, D.W.; Lee, J.; Pearce, L.V.; Pavlyukovets, V.A.; Morgan, M.A.; Tran, R.; Toth, A.; Lundberg, D.J.; Blumberg, P.M. Stereospecific high-affinity TRPV1 antagonists: Chiral N-(2-Benzyl-3-pivaloyloxypropyl) 2-[4-(methylsulfonylamino)phenyl] propionamide analogues. J. Med. Chem., 2008, 51, 57-67.