Design and Synthesis of Indole-Based Peptoids as Potent Noncompetitive Antagonists of Transient Receptor Potential Vanilloid 1 Martina Quintanar-Audelo, ² Asia Ferna ´ndez-Carvajal, ‡ Wim Van Den Nest, § Cristina Carren ˜o, § Antonio Ferrer-Montiel,* ,‡ and Fernando Albericio* ,², | IRB Barcelona, Barcelona Science Park, UniVersity of Barcelona, and Department of Organic Chemistry, 08028 Barcelona, Spain, Institute of Molecular and Cellular Biology, UniVersity Miguel Herna ´ ndez, 03202 Alicante, Spain, and DiVerDrugs SL, 08850 GaVa ` , Barcelona, Spain ReceiVed May 26, 2007 The vanilloid receptor subunit 1, or transient receptor potential vanilloid 1 (TRPV1), integrates physical and chemical stimuli in the peripheral nervous system, playing a key role in inflammatory pain. Identification of potent TRPV1 antagonists is thus an important goal of current neuropharmacology. Herein, we describe the solid-phase synthesis of a series of indole-based peptoids (N-alkylglycines) and the biological activity of the peptoids as novel TRPV1 antagonists. The potency and selectivity of the compounds were determined by electrophysiological recordings in Xenopus oocytes. The most potent and selective noncompetitive TRPV1 antagonist of the series, compound 7, represents an interesting pharmacophoric structure for analgesic lead optimization. Introduction Organisms require pain to survive and to maintain structural integrity, but sustained or chronic pain can result in side effects and in a decreased quality of life. Inflammatory pain is a response to tissue damage. It begins when noxious stimuli (thermal, chemical, or mechanical) excite sensory neurons called nociceptors. 1-4 Nociceptors are sensitized by activation of PKC a and PKA pathways, which leads to phosphorylation of sensory receptors involved in the nociceptive function. 5 The resultant sensory signaling is conveyed to the spinal cord and, finally, to specific brain regions, leading to the sensation of pain. 6 There is evidence that peripheral sensitization is mediated by hyper- excitation of TRPV1 receptors. Identification of TRPV1 as a molecular integrator of noxious stimuli that involves both thermal nociception and inflammatory hyperalgesia has validated it as a key therapeutic target for inflammatory pain. 7-12 TRPV1 was first reported by Caterina et al. 13 as a capsaicin (1) receptor, a nonselective cation channel activated by vanilloids and lipids, and gated at temperatures above 43 °C. In addition, mild extracellular pH potentiates its activation by noxious heat and vanilloids, whereas strongly acidic conditions (pH <6) directly activate the channel. 14,15 Furthermore, the channel is notably sensitized by proalgesic substances released during inflammation. 16 TRPV1 hyperstimulation by capsaicin leads to long-term desensitization of the sensory neurons and thus produces an analgesic effect. Capsaicin is the active component of various topical pain relievers and has been used to treat pain associated with diabetic neuropathy and arthritis. 17,18 However, the clinical use of TRPV1 agonists (See Figure 1), such as 1 and resiniferatoxin (RTX, 2), is limited due to side effects (burning sensation, irritation, and neurotoxicity) resulting from continuous influx of Ca 2+ into the cells. Structure-activity relationship (SAR) studies of vanilloids have led to other potent drugs. 19 However, these also exhibit irritant side effects. An alternative approach to pain relief is to block the TRPV1- mediated pain signaling pathways with receptor antagonists, a promising strategy for the development of novel analgesic drugs with potentially fewer side effects. 20 In addition, some TRPV1 antagonists have shown positive effects in animal models of neurophatic pain, which makes these kinds of compounds very attractive as analgesic molecules. 21 During the past few years, several classes of competitive TRPV1 antagonists, either structurally related or not to 1 or 2, have been described, and their chemistry and pharmacology have been reviewed. 22-25 Many of these antagonists are focused on structures containing * To whom correspondence should be addressed. A.F.-M.: phone, 0034 966658727; fax, 0034 966658758; e-mail, aferrer@umh.es. F.A.: phone, 0034 934037088; fax, 0034 934037126; e-mail, albericio@pcb.ub.es. ² IRB Barcelona, Barcelona Science Park, University of Barcelona. ‡ University Miguel Herna ´ndez. § DiverDrugs SL. | Department of Organic Chemistry, University of Barcelona. a Abbreviations: BAL, backbone amide linker; MTBD, 1,3,4,6,7,8- hexahydro-1-methyl-2H-pyrimido[1,2-a]pyrimidine; NMDA, N-methyl-D- aspartate; PKA, protein kinase A; PKC, protein kinase C; TES, 2-[(2- hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]ethanesulfonic acid; TRPV1, transient receptor potential vanilloid 1; abbreviations used for amino acids follow the IUPAC-IUB Comission of Biochemical Nomenclature (Jones, J. H. J. Pept. Sci. 2003, 9,1-8). Figure 1. Chemical structures of TRPV1 agonists and antagonists. 6133 J. Med. Chem. 2007, 50, 6133-6143 10.1021/jm070612v CCC: $37.00 © 2007 American Chemical Society Published on Web 11/07/2007