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Capsaicin receptor antagonists: a promising new addition to the pain clinic

2009; Elsevier BV; Volume: 102; Issue: 2 Linguagem: Inglês

10.1093/bja/aen354

1471-6771

David G. Lambert,

Ion channel regulation and function

Capsaicin is the pungent vanilloid found in chilli peppers. Sensitivity to this substance has been used for many years to identify nociceptive fibres. These are predominantly unmyelinated C fibres with slow conduction velocity but also a small number of myelinated Aδ fibres. The cell bodies of these fibres lie in the dorsal root and trigeminal ganglia. The latter is involved in the pathogenesis of migraine. It is now well established that capsaicin activates a specific member of the transient receptor potential ligand-gated ion channel family, TRPV1 (previously known as the vanilloid receptor, VR1). The endogenous activators for this receptor are noxious heat (>43°C), protons (acidosis, pH 5–6), the endocannabinoid anandamide, and a range of other putatives including NADA (N-arachidonoyl-dopamine). There is also evidence for a central role of TRPV1 receptors including an interaction with dopaminergic neurones. The roles and activators of TRPV1 receptors have been the subject of reviews.1Szallasi A Blumberg PM Vanilloid (Capsaicin) receptors and mechanisms.Pharmacol Rev. 1999; 51: 159-212PubMed Google Scholar, 2Tominaga M Tominaga T Structure and function of TRPV1.Pflugers Arch. 2005; 451: 143-150Crossref PubMed Scopus (352) Google Scholar, 3Szallasi A Small molecule vanilloid TRPV1 receptor antagonists approaching drug status: can they live up to the expectations?.Naunyn Schmiedebergs Arch Pharmacol. 2006; 373: 273-286Crossref PubMed Scopus (39) Google Scholar, 4Szallasi A Cruz F Geppetti P TRPV1: a therapeutic target for novel analgesic drugs?.Trends Mol Med. 2006; 12: 545-554Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, 5Szallasi A Cortright DN Blum CA Eid SR The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept.Nat Rev Drug Discov. 2007; 6: 357-372Crossref PubMed Scopus (715) Google Scholar The polymodal activation profile in response to heat and acidosis, coupled with modulation by several other inflammatory mediators, especially prostaglandins and bradykinin, has led to TRPV1 receptors being described as integrators of inflammatory signalling.6Cortright DN Szallasi A Biochemical pharmacology of the vanilloid receptor TRPV1. An update.Eur J Biochem. 2004; 271: 1814-1819Crossref PubMed Scopus (287) Google Scholar TRPV1 receptor activation leads to an influx of Ca2+ and prolonged application of an agonist, such as capsaicin, leads to release of central transmitters (glutamate and substance P) from nociceptive afferents and a desensitization of the channel. As a consequence of exhaustion of transmitters and desensitization, the afferent becomes ‘chemically denervated’ and functionally silent. This is the basis for the well-established use of capsaicin cream in clinical settings where efficacy has been reported in osteoarthritis, diabetic neuropathy, and psoriasis.7Zhang WY Li Wan Po A The effectiveness of topically applied capsaicin. A meta-analysis.Eur J Clin Pharmacol. 1994; 46: 517-522Crossref PubMed Scopus (264) Google Scholar There is also evidence of effectiveness in post-herpetic neuralgia and post-mastectomy pain.7Zhang WY Li Wan Po A The effectiveness of topically applied capsaicin. A meta-analysis.Eur J Clin Pharmacol. 1994; 46: 517-522Crossref PubMed Scopus (264) Google Scholar 8Available from www.medicine.ox.ac.uk/bandolier/band29/b29-6.htmlGoogle Scholar The problem with capsaicin, as is well known, is that application produces an intense burning sensation and thus compliance can be a problem (Table 1).Table 1Comparison of TRPV1 agonist and antagonist strategies for use in the clinic. *Activated/modulated by acidosis, increased heat, and other inflammatory mediators. †In various stages of clinical evaluation. ‡Used in urology via intravesical instillation. Efficacy is questionable at best. ¶Clinical trials summarized in the work of Szallasi and colleagues5 and from Glenmark21 and AstraZeneca.22 §Numbers needed to treat (NNT with 95% confidence interval).7 8 SB705498, N-(2-bromophenyl)-N′-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea. NGD8243, structure not disclosed. AMG517: N-(4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl)-acetamideI. GRC6211, structure not disclosed. AZD1386: structure not disclosedAgonistAntagonistMode of actionTransmitter release and TRPV1 desensitizationInhibition of up-regulated TRPV1 receptors activated during inflammation*Chemical denervationClinical drugsCapsaicin cream†SB705498, NDG8243, AMG517, GRC6211, and AZD1386Resiniferatoxin‡Clinical indicationsOsteoarthritisSB705498 phase II migraine, phase I dental pain¶0.025–0.075% q.d.s. 4/52 NNT 3.4(2.6–4.8)§NGD8243 phase II cough¶Diabetic neuropathyAMG517 phase I pain¶0.075% q.d.s. 4–8/52 NNT 4.2(2.9–7.5)§GRC6211 phase II range of pains including osteoarthritis, dental, and neuropathic¶PsoriasisAZD1386 phase II chronic nociceptive pain¶0.025% q.d.s. 4–6/52 NNT 3.9(2.7–7.4)§DisadvantagesIntense burning leading to reduced complianceAntagonism of all TRPV1 signallingNo oral formulation(Studies difficult to blind)AdvantagesDepending on dose–long-lasting effectNo initial irritationOral formulationPotential for good compliance Open table in a new tab There is now a body of evidence in support of TRPV1 receptor up-regulation in disease. For example, in experimental animals, there is an up-regulation in inflammatory hyperalgesia,9Wilson-Gerwing TD Dmyterko MV Zochodne DW Johnston JM Verge VM Neurotrophin-3 suppresses thermal hyperalgesia associated with neuropathic pain and attenuates transient receptor potential vanilloid receptor-1 expression in adult sensory neurons.J Neurosci. 2005; 25: 758-767Crossref PubMed Scopus (85) Google Scholar osteoarthritis,10Fernihough J Gentry C Bevan S Winter J Regulation of calcitonin gene-related peptide and TRPV1 in a rat model of osteoarthritis.Neurosci Lett. 2005; 388: 75-80Crossref PubMed Scopus (121) Google Scholar and cancer-induced bone pain (see below). Interestingly, in animals with genetic deletion of TRPV1 receptors, the symptoms of experimental arthritis are reduced.11Barton NJ McQueen DS Thomson D et al.Attenuation of experimental arthritis in TRPV1R knockout mice.Exp Mol Pathol. 2006; 81: 166-170Crossref PubMed Scopus (74) Google Scholar In this case, deletion of the receptor represents an extreme form of ‘antagonism’. In humans, there are data showing up-regulation of TRPV1 in a wide range of conditions including inflamed bowel, vulvodynia, mastalgia, neurogenic bladder,4Szallasi A Cruz F Geppetti P TRPV1: a therapeutic target for novel analgesic drugs?.Trends Mol Med. 2006; 12: 545-554Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, 5Szallasi A Cortright DN Blum CA Eid SR The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept.Nat Rev Drug Discov. 2007; 6: 357-372Crossref PubMed Scopus (715) Google Scholar and dental pulp inflammation.12Morgan CR Rodd HD Clayton N Davis JB Boissonade FM Vanilloid receptor 1 expression in human tooth pulp in relation to caries and pain.J Orofac Pain. 2005; 19: 248-260PubMed Google Scholar This up-regulation of receptor numbers and function, coupled with initial irritation when using TRPV1 agonists (like capsaicin) and the limited agonist formulation options (e.g., topical cream), forms the basis on which the antagonist strategy has been developed. In this issue of the British Journal of Anaesthesia, Niiyama and colleagues13Niiyama Y Kawamata T Yamamoto J Furuse S Namiki A SB366791, a TRPV1 antagonist, potentiates analgesic effects of systemic morphine in a murine model of bone cancer pain.Br J Anaesth. 2009; 102: 251-258Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar describe the use of the selective TRPV1 antagonist SB-366791 [N-(3-methoxyphenyl)-4-chlorocinnamide] in an animal model of bone cancer pain. Mice were injected with NCTC 2472 osteolytic sarcoma cells directly into the femur and then assessed over a 2 h period for pain-related behaviours (limb use, spontaneous flinches, and weight-bearing). Animals received intraperitoneal morphine (1, 3, and 10 mg kg−1) or intraperitoneal SB-366791 (0.1, 0.3, and 1 mg kg−1) alone, or in various combinations. Sarcoma implantation produced an increase in pain-related behaviours. Morphine was effective only at the higher dose of 10 mg kg−1 and SB-366791 was effective alone at 0.3 and 1 mg kg−1. Importantly, SB-366791 at a dose of 0.1 mg kg−1, which on its own was ineffective, resulted in morphine antinociception at all doses tested. The authors have previously shown with this model that μ-opioid receptors on TRPV1 positive afferents are down-regulated.14Yamamoto J Kawamata T Niiyama Y Omote K Namiki A Down-regulation of mu opioid receptor expression within distinct subpopulations of dorsal root ganglion neurons in a murine model of bone cancer pain.Neuroscience. 2008; 151: 65-72Crossref Scopus (76) Google Scholar This down-regulation is likely to be the cause of the reduced morphine efficacy. The authors have also demonstrated an up-regulation of TRPV1 receptors15Niiyama Y Kawamata T Yamamoto J Omote K Namiki A Bone cancer increases transient receptor potential vanilloid subfamily 1 expression within distinct subpopulations of dorsal root ganglion neurons.Neuroscience. 2007; 148: 560-572Crossref PubMed Scopus (101) Google Scholar and have therefore suggested that reduced morphine efficacy could be rescued by switching off up-regulated TRPV1 receptors. Although SB-366791 is an interesting experimental tool, antagonists suitable for clinical development are required to evaluate the role of TRPV1 antagonism in human pain. There are now a wide range of such molecules in various stages of development (Table 1). SB-705498 (N-(2-bromophenyl)-N′-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea) is a novel, selective (screened against 39 targets), and potent TRPV1 antagonist capable of inhibiting capsaicin, acid, and heat-evoked activation.16Gunthorpe MJ Hannan SL Smart D et al.Characterization of SB-705498, a potent and selective vanilloid receptor-1 (VR1/TRPV1) antagonist that inhibits the capsaicin-, acid-, and heat-mediated activation of the receptor.J Pharmacol Exp Ther. 2007; 321: 1183-1192Crossref PubMed Scopus (86) Google Scholar In addition, this antagonist displayed good oral bioavailability in rat, guinea pig, and dog.17Rami HK Thompson M Stemp G et al.Discovery of SB-705498: a potent, selective and orally bioavailable TRPV1 antagonist suitable for clinical development.Bioorg Med Chem Lett. 2006; 16: 3287-3291Crossref PubMed Scopus (123) Google Scholar When administered to healthy human volunteers, a single oral dose of 400 mg (the study used a variety of doses up to 400 mg) resulted in peak plasma concentrations of ∼1.2 μg ml−1 some 0.75–4 h after dosing. In this pharmacokinetic analysis, the most common adverse reaction was headache (31.6% in treatment and 15.8% in placebo), but others included contact dermatitis (10.5% in treatment and 21.1% in placebo; the authors attribute dermatitis to application of dressings/ECG electrodes) and dizziness (5.3% in both groups). These were not dose-related. SB-705498 was effective against UVB irradiation-induced thermal pain, sensitization, and flare and capsaicin-evoked hyperalgesia and flare in volunteers.18Chizh BA O'Donnell MB Napolitano A et al.The effects of the TRPV1 antagonist SB-705498 on TRPV1 receptor-mediated activity and inflammatory hyperalgesia in humans.Pain. 2007; 132: 132-141Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar There are phase II clinical trials of this antagonist in migraine, dental pain, and irritable bowel syndrome (terminated for the latter indication).19Available from http://gsk-clinicalstudyregister.com/protocolcomp_list.jsp?compound=Sb705498&studyType=All&phase=All&population=All&marketing=All&status=All&country=AllGoogle Scholar A further orally active antagonist (SB-782443) (GlaxoSmithKline) is in clinical development.20Westaway SM Thompson M Rami HK et al.Design and synthesis of 6-phenylnicotinamide derivatives as antagonists of TRPV1.Bioorg Med Chem Lett. 2008; 18: 5609-5613Crossref PubMed Scopus (42) Google Scholar Some of the other TRPV1 antagonists currently in clinical development are noted in Table 1, but there is little published information. These antagonists include GRC6211 (Glenmark) which is in phase II trials for osteoarthritic pain, incontinence, and neuropathic pain,21Available from http://www.glenmarkpharma.com/research/clinical.htmlGoogle Scholar AZD1386 (AstraZeneca) in phase II for chronic nociceptive pain and phase I for gastroesophageal reflux disease,22Available from http://www.astrazeneca.com/article/511390.aspxGoogle Scholar and NGD8243 (Neurogen Corporation) in phase II for cough.23Available from http://www.neurogen.com/products/vr1index.htmGoogle Scholar From an anaesthetic perspective, this interesting paper13Niiyama Y Kawamata T Yamamoto J Furuse S Namiki A SB366791, a TRPV1 antagonist, potentiates analgesic effects of systemic morphine in a murine model of bone cancer pain.Br J Anaesth. 2009; 102: 251-258Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar should be viewed in the wider context of TRPV1 antagonists as a novel class of analgesic agents. As TRPV1 receptors ‘integrate’, pain signalling antagonizing this receptor should have activity at a range of pains including chronic pain. In addition, as the paper13Niiyama Y Kawamata T Yamamoto J Furuse S Namiki A SB366791, a TRPV1 antagonist, potentiates analgesic effects of systemic morphine in a murine model of bone cancer pain.Br J Anaesth. 2009; 102: 251-258Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar suggests, TRPV1 antagonism may breathe new life into morphine. There are now sufficient data on TRPV1 receptor antagonists to suggest that they have a promising future in the pain clinic. As part of a TRPV1 collaboration with GSK, DGL has received research reagents and used the R&D facility in Harlow. Work on TRPV1 receptors in his laboratory has been funded by British Journal of Anaesthesia/Royal College of Anaesthetists.