Antihyperalgesic Effects of (R,E)-N-(2-Hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)-acrylamide (AMG8562), a Novel Transient Receptor Potential Vanilloid Type 1 Modulator That Does Not Cause Hyperthermia in Rats

Abstract

Antagonists of the vanilloid receptor TRPV1 (transient receptor potential vanilloid type 1) have been reported to produce antihyperalgesic effects in animal models of pain. These antagonists, however, also caused concomitant hyperthermia in rodents, dogs, monkeys, and humans. Antagonist-induced hyperthermia was not observed in TRPV1 knockout mice, suggesting that the hyperthermic effect is exclusively mediated through TRPV1. Since antagonist-induced hyperthermia is considered a hurdle for developing TRPV1 antagonists as therapeutics, we investigated the possibility of eliminating hyperthermia while maintaining antihyperalgesia. Here, we report four potent and selective TRPV1 modulators with unique in vitro pharmacology profiles (profiles A through D) and their respective effects on body temperature. We found that profile C modulator, (R,E)-N-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)acrylamide (AMG8562), blocks capsaicin activation of TRPV1, does not affect heat activation of TRPV1, potentiates pH 5 activation of TRPV1 in vitro, and does not cause hyperthermia in vivo in rats. We further profiled AMG8562 in an on-target (agonist) challenge model, rodent pain models, and tested for its side effects. We show that AMG8562 significantly blocks capsaicin-induced flinching behavior, produces statistically significant efficacy in complete Freund's adjuvant-and skin incision-induced thermal hyperalgesia, and acetic acid-induced writhing models, with no profound effects on locomotor activity. Based on the data shown here, we conclude that it is feasible to modulate TRPV1 in a manner that does not cause hyperthermia while maintaining efficacy in rodent pain models.The vanilloid receptor TRPV1 emerged as a therapeutic target for pain based on the fact that 1) TRPV1 agonists cause pain (Szallasi and Blumberg, 1999;Jones et al., 2004), 2) TRPV1 expression is up-regulated during painful conditions (Ji et al., 2002;Matthews et al., 2004), 3) TRPV1 knockout mice display attenuated pain behaviors (Caterina et al., 2000;Davis et al., 2000;Keeble et al., 2005), and 4) TRPV1 antagonists reverse AMG 517,

TRPV1 dans les neuropathies douloureuses

“…Profil D : molécules qui inhibent l'activation par la capsaïcine et potentialisent l'activation par un pH < 5 et la chaleur [28]. Pour la définition du profil voir [29].…”

TRPV1 Antagonists as Analgesic Agents

“…However, not unexpectedly, some of these new TRPV1 blockers turned out to be stimulus-specific whereas others appear to block several means of activation [92,93]. For instance, AMG0610 (from Amgen) and SB-366791 (developed by GlaxoSmithKline) inhibit the activation of rat TRPV1 by capsaicin but not by acid, whereas I-RTX, BCTC, AMG6880, AMG7472, AMG9810 and A-425619 are TRPV1 antagonists that do not differentiate between capsaicin and protons [92,[94][95][96].…”

“…Compounds (e.g. AMG8562) that prevented the activation of rat TRPV1 by capsaicin, but not by low pH (referred to as Profile C antagonists), had no effect on body temperature [93]. Finally, the Abbott group disclosed that acid sparing TRPV1 antagonists do not significantly increase core body temperature [127].…”

“…For instance, AMG0610 (from Amgen) and SB-366791 (developed by GlaxoSmithKline) inhibit the activation of rat TRPV1 by capsaicin but not by acid, whereas I-RTX, BCTC, AMG6880, AMG7472, AMG9810 and A-425619 are TRPV1 antagonists that do not differentiate between capsaicin and protons [92,[94][95][96]. Compound AMG8562 does not block heat-evoked activation of rat TRPV1 [93]. Other potent and selective TRPV1 antagonists of both human and rat TRPV1 receptors, the 1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)urea, A-425619 (Abbott) and compound PHE377 (PharmEste), proved dose dependently effective in several models of inflammatory and neuropathic pain without altering motor and memory/learning performances [107,108].…”

Positive allosteric modulation of TRPV1 as a novel analgesic mechanism

“…Extensive drug development has been directed at generating antagonists of the TRPV1 orthosteric capsaicinbinding site for acute and chronic pain. This research yielded many outstanding pharmacological agents in several chemical classes [23] that include, for example, ABT-102 [24], SB-705498 [25], AS1928370 [26], and AMG8562 [27]. However, as a class, this group of antagonists encountered difficulties in transitioning to clinical utilization due to two main side effects.…”