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Nuria A Tamayo,
Yunxin Bo,
Vijay Gore,
Vu Ma,
Nobuko Nishimura,
Phi Tang, Hong Deng,
Lana Klionsky,
Sonya G Lehto,
Weiya Wang,
Brad Youngblood,
Jiyun Chen,
Tiffany L Correll,
Michael D Bartberger,
Narender R Gavva,
Mark H Norman
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ABSTRACT: The transient receptor potential melastatin type 8 (TRPM8) is a nonselective cation channel primarily expressed in a subpopulation of sensory neurons that can be activated by a wide range of stimuli, including menthol, icilin, and cold temperatures (<25 °C). Antagonism of TRPM8 is currently under investigation as a new approach for the treatment of pain. As a result of our screening efforts, we identified tetrahydrothienopyridine 4 as an inhibitor of icilin-induced calcium influx in CHO cells expressing recombinant rat TRPM8. Exploration of the structure-activity relationships of 4 led to the identification of a potent and orally bioavailable TRPM8 antagonist, tetrahydroisoquinoline 87. Compound 87 demonstrated target coverage in vivo after oral administration in a rat pharmacodynamic model measuring the prevention of icilin-induced wet-dog shakes (WDS).
Journal of Medicinal Chemistry 02/2012; 55(4):1593-611. · 4.80 Impact Factor
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BaoXi Gao,
Markus Hierl,
Kristie Clarkin,
Todd Juan,
Hung Nguyen,
Marissa van der Valk, Hong Deng,
Wenhong Guo,
Sonya G Lehto,
David Matson, [......],
Kevin Gaida,
Lei Cao,
Dan Waldon,
Brian K Albrecht,
Alessandro A Boezio,
Katrina W Copeland,
Jean-Christophe Harmange,
Stephanie K Springer,
Annika B Malmberg,
Stefan I McDonough
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ABSTRACT: Nicotinic acetylcholine receptors (nAChRs) are longstanding targets for a next generation of pain therapeutics, but the nAChR subtypes that govern analgesia remain unknown. We tested a series of nicotinic agonists, including many molecules used or tried clinically, on a panel of cloned neuronal nAChRs for potency and selectivity using patch-clamp electrophysiology and a live cell-based fluorescence assay. Nonselective nicotinic agonists as well as compounds selective either for alpha4beta2 or for alpha7 nAChRs were then tested in the formalin and complete Freund's adjuvant models of pain. Nonselective nAChR agonists ABT-594 and varenicline were effective analgesics. By contrast, the selective alpha4beta2 agonist ispronicline and a novel alpha4beta2-selective potentiator did not appear to produce analgesia in either model. alpha7-selective agonists reduced the pain-related endpoint, but the effect could be ascribed to nonspecific reduction of movement rather than to analgesia. Neither selective nor nonselective alpha7 nicotinic agonists affected the release of pro-inflammatory cytokines in response to antigen challenge. Electrophysiological recordings from spinal cord slice showed a strong nicotine-induced increase in inhibitory synaptic transmission that was mediated partially by alpha4beta2 and only minimally by alpha7 subtypes. Taken with previous studies, the results suggest that agonism of alpha4beta2 nAChRs is necessary but not sufficient to produce analgesia, and that the spinal cord is a key site where the molecular action of nAChRs produces analgesia.
Pain 02/2010; 149(1):33-49. · 5.78 Impact Factor
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Sonya G Lehto,
Rami Tamir, Hong Deng,
Lana Klionsky,
Rongzhen Kuang,
April Le,
Doo Lee,
Jean-Claude Louis,
Ella Magal,
Barton H Manning, [......],
Nuria Tamayo,
Tingrong Wang,
Judy Wang,
Jue Wang,
Weiya Wang,
Brad Youngblood,
Maosheng Zhang,
Dawn Zhu,
Mark H Norman,
Narender R Gavva
[show abstract]
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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.
Journal of Pharmacology and Experimental Therapeutics 08/2008; 326(1):218-29. · 3.83 Impact Factor
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Narender R Gavva,
Anthony W Bannon,
Sekhar Surapaneni,
David N Hovland,
Sonya G Lehto,
Anu Gore,
Todd Juan, Hong Deng,
Bora Han,
Lana Klionsky,
Rongzhen Kuang,
April Le,
Rami Tamir,
Jue Wang,
Brad Youngblood,
Dawn Zhu,
Mark H Norman,
Ella Magal,
James J S Treanor,
Jean-Claude Louis
[show abstract]
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ABSTRACT: The vanilloid receptor TRPV1 (transient receptor potential vanilloid 1) is a cation channel that serves as a polymodal detector of pain-producing stimuli such as capsaicin, protons (pH <5.7), and heat. TRPV1 antagonists block pain behaviors in rodent models of inflammatory, neuropathic, and cancer pain, suggesting their utility as analgesics. Here, we report that TRPV1 antagonists representing various chemotypes cause an increase in body temperature (hyperthermia), identifying a potential issue for their clinical development. Peripheral restriction of antagonists did not eliminate hyperthermia, suggesting that the site of action is predominantly outside of the blood-brain barrier. Antagonists that are ineffective against proton activation also caused hyperthermia, indicating that blocking capsaicin and heat activation of TRPV1 is sufficient to produce hyperthermia. All TRPV1 antagonists evaluated here caused hyperthermia, suggesting that TRPV1 is tonically activated in vivo and that TRPV1 antagonism and hyperthermia are not separable. TRPV1 antagonists caused hyperthermia in multiple species (rats, dogs, and monkeys), demonstrating that TRPV1 function in thermoregulation is conserved from rodents to primates. Together, these results indicate that tonic TRPV1 activation regulates body temperature.
Journal of Neuroscience 03/2007; 27(13):3366-74. · 7.11 Impact Factor
