High throughput screening using the recombinant human TRPV1 receptor was used to identify a series of pyridinylpiperazine ureas (3) as TRPV1 vanilloid receptor ligands. Exploration of the structure-activity relationships by parallel synthesis identified the essential pharmacophoric elements for antagonism that permitted further optimization via targeted synthesis to provide a potent orally bioavailable and selective TRPV1 modulator 41 active in several in vivo models.

The nonselective cation channel TRPA1 (ANKTM1, p120) is a potential mediator of pain, and selective pharmacological modulation of this channel may be analgesic. Although several TRPA1 activators exist, these tend to be either reactive or of low potency and/or selectivity. The aim of the present study, therefore, was to identify novel TRPA1 agonists. Using a combination of calcium fluorescent assays and whole-cell electrophysiology, we discovered several compounds that possess potent, selective TRPA1-activating activity, including several lipid compounds (farnesyl thiosalicylic acid, farnesyl thioacetic acid, 15-deoxy-Delta(12,14)-prostaglandin J(2), and 5,8,11,14-eicosatetraynoic acid), and two marketed drugs: disulfiram (Antabuse; a compound used in the treatment of alcohol abuse) and the antifungal agent chlordantoin. Farnesyl thiosalicylic acid activates the channel in excised patches and in the absence of calcium. Furthermore, using a quadruple TRPA1 mutant, we show that the mechanism of action of farnesyl thiosalicylic acid differs from that of the reactive electrophilic reagent allylisothiocyanate. As a TRPA1 agonist with a potentially novel mechanism of action, farnesyl thiosalicylic acid may be useful in the study of TRPA1 channels.

The authors used the PatchXpress ® 7000A system to measure compound activity at the hERG channel using procedures that mimicked the "gold-standard" conventional whole-cell patch clamp. A set of 70 compounds, including hERG antagonists with potencies spanning 3 orders of magnitude, were tested on hERG302-HEK cells using protocols aimed at either identifying compound activity at a single concentration or obtaining compound potency from a cumulative concentration dependence paradigm. After exposure to compounds and subsequent washout of the wells to determine reversibility of the block, blockade by a reference compound served as a quality control. Electrical parameters and voltage dependence were similar to those obtained using a conventional whole-cell patch clamp. Rank order of compound potency was also comparable to that determined by conventional methods. One exception was flunarizine, a particularly lipophilic compound. The PatchXpress ® accurately identified the activity of 29 moderately potent antagonists, which only weakly displace radiolabeled astemizole and are false negatives in the binding assay. Finally, no false hits were observed from a collection of relatively inactive compounds. High-quality data acquisition by PatchXpress ® should help accelerate secondary screening for ion channel modulators and the drug discovery process. (Journal of Biomolecular Screening 2005:168-181)

Transient receptor potential vanilloid 1 (TRPV1) plays an integral role in modulating the cough reflex, and it is an attractive antitussive drug target. The purpose of this study was to characterize a TRPV1 antagonist, 4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid (5-trifluoromethyl-pyridin-2-yl)-amide (JNJ17203212), against the guinea pig TRPV1 receptor in vitro followed by a proof-of-principle study in an acid-induced model of cough. The affinity of JNJ17203212 for the recombinant guinea pig TRPV1 receptor was estimated by radioligand binding, and it was functionally characterized by antagonism of low-pH and capsaicin-induced activation of the ion channel (fluorometric imaging plate reader and electrophysiology). The nature of antagonism was further tested against the native channel in isolated guinea pig tracheal rings. Following pharmacokinetic characterization of JNJ17203212 in guinea pigs, pharmacodynamic and efficacy studies were undertaken to establish the antitussive efficacy of the TRPV1 antagonist. The pK i of JNJ17203212 for recombinant guinea pig TRPV1 was 7.14 Ϯ 0.06. JNJ17203212 inhibited both pH (pIC 50 of 7.23 Ϯ 0.05) and capsaicin (pIC 50 of 6.32 Ϯ 0.06)-induced channel activation. In whole-cell patch clamp, the pIC 50 for inhibition of guinea pig TRPV1 was 7.3 Ϯ 0.01. JNJ17203212 demonstrated surmountable antagonism in isolated trachea, with a pK B value of 6.2 Ϯ 0.1. Intraperitoneal administration of 20 mg/kg JNJ17203212 achieved a maximal plasma exposure of 8.0 Ϯ 0.4 M, and it attenuated capsaicin evoked coughs with similar efficacy to codeine (25 mg/kg). Last, JNJ17203212 dose-dependently produced antitussive efficacy in citric acid-induced experimental cough in guinea pigs. Our data provide preclinical support for developing TRPV1 antagonists for the treatment of cough.The transient receptor potential vanilloid 1 (TRPV1 or VR1) receptor is a ligand-gated cation channel that is activated or modulated by a variety of mediators thought to contribute to neuroinflammation (Tominaga and Tominaga, 2005;Szallasi et al., 2007). This ion channel is a polymodal nociceptor that is activated by vanilloids such as capsaicin (Caterina et al., 1997), noxious heat (Cesare et al., 1999), low pH, polyamines (Ahern et al., 2006), and lipid mediators such as anandamide (Ross, 2003;De Petrocellis and Di Marzo, 2005), to mention a few. In addition, various endogenous mediators such as bradykinin, substance P, glutamate, prostaglandins, and ATP sensitize TRPV1 (Szallasi et al., 2007). As an integrator and mediator of nociceptive and/or inflammatory stimuli, TRPV1 is an attractive therapeutic target for the treatment of various neuroinflammatory disorders (Jia et Article, publication date, and citation information can be found at

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A series of title compounds of type (I), (II) and (III) is prepared as potent antagonists of human vanilloid receptor 1 (VR1). The structure-activity relationships of the series are discussed. -(JETTER, M. C.; YOUNGMAN, M. A.; MCNALLY, J. J.; ZHANG, S.-P.; DUBIN, A. E.; NASSER, N.; DAX*, S. L.; Bioorg.