Browsing by Author "Snutch, Terrance Preston"

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    A novel slow-inactivation-specific ion channel modulator attenuates neuropathic pain
    (Elsevier, 2011-04-01) Hildebrand, Michael E.; Smith, Paula L.; Bladen, Chris; Eduljee, Cyrus; Xie, Jennifer Yanhua; Chen, Lina; Fee-Maki, Molly; Doering, Clinton J.; Mezeyova, Janette; Zhu, Yongbao; Belardetti, Francesco; Pajouhesh, Hassan; Parker, David B.; Arnerić, Stephen Peter; Parmar, Manjeet; Porreca, Frank; Tringham, Elizabeth W.; Zamponi, Gerald W.; Snutch, Terrance Preston
    Voltage-gated ion channels are implicated in pain sensation and transmission signaling mechanisms within both peripheral nociceptors and the spinal cord. Genetic knockdown and knockout experiments have shown that specific channel isoforms, including Na(V)1.7 and Na(V)1.8 sodium channels and Ca(V)3.2 T-type calcium channels, play distinct pronociceptive roles. We have rationally designed and synthesized a novel small organic compound (Z123212) that modulates both recombinant and native sodium and calcium channel currents by selectively stabilizing channels in their slow-inactivated state. Slow inactivation of voltage-gated channels can function as a brake during periods of neuronal hyperexcitability, and Z123212 was found to reduce the excitability of both peripheral nociceptors and lamina I/II spinal cord neurons in a state-dependent manner. In vivo experiments demonstrate that oral administration of Z123212 is efficacious in reversing thermal hyperalgesia and tactile allodynia in the rat spinal nerve ligation model of neuropathic pain and also produces acute antinociception in the hot-plate test. At therapeutically relevant concentrations, Z123212 did not cause significant motor or cardiovascular adverse effects. Taken together, the state-dependent inhibition of sodium and calcium channels in both the peripheral and central pain signaling pathways may provide a synergistic mechanism toward the development of a novel class of pain therapeutics.
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    Selective inhibition of Cav3.3 T-type calcium channels by Galphaq/11-coupled muscarinic acetylcholine receptors
    (The American Society for Biochemistry and Molecular Biology, Inc., 2007-07-20) Hildebrand, Michael E.; David, Laurence S.; Hamid, Jawed; Mulatz, Kirk J.; García, Esperanza; Zamponi, Gerald W.; Snutch, Terrance Preston
    T-type calcium channels play critical roles in controlling neuronal excitability, including the generation of complex spiking patterns and the modulation of synaptic plasticity, although the mechanisms and extent to which T-type Ca(2+) channels are modulated by G-protein-coupled receptors (GPCRs) remain largely unexplored. To examine specific interactions between T-type Ca(2+) channel subtypes and muscarinic acetylcholine receptors (mAChRS), the Cav3.1 (alpha(1G)), Cav3.2 (alpha(1H)), and Cav3.3 (alpha) T-type Ca(2+)(1I)channels were co-expressed with the M1 Galpha(q/11)-coupled mAChR. Perforated patch recordings demonstrate that activation of M1 receptors has a strong inhibitory effect on Cav3.3 T-type Ca(2+) currents but either no effect or a moderate stimulating effect on Cav3.1 and Cav3.2 peak current amplitudes. This differential modulation was observed for both rat and human T-type Ca(2+) channel variants. The inhibition of Cav3.3 channels by M1 receptors is reversible, use-independent, and associated with a concomitant increase in inactivation kinetics. Loss-of-function experiments with genetically encoded antagonists of Galpha and Gbetagamma proteins and gain-of-function experiments with genetically encoded Galpha subtypes indicate that M1 receptor-mediated inhibition of Cav3.3 occurs through Galpha(q/11). This is supported by experiments showing that activation of the M3 and M5 Galpha(q/11)-coupled mAChRs also causes inhibition of Cav3.3 currents, although Galpha(i)-coupled mAChRs (M2 and M4) have no effect. Examining Cav3.1-Cav3.3 chimeric channels demonstrates that two distinct regions of the Cav3.3 channel are necessary and sufficient for complete M1 receptor-mediated channel inhibition and represent novel sites not previously implicated in T-type channel modulation.
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    Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors
    (Elsevier, 2012-04-19) Pajouhesh, Hassan; Feng, Zhong-Ping; Zhang, Lingyun; Pajouhesh, Hossein; Jiang, Xinpo; Dong, Haiheng; Ding, Yanbing; Porreca, Frank; Belardetti, Francesco; Hendricson, Adam W.; Tringham, Elizabeth W.; Vanderah, Todd W.; Zamponi, Gerald W.; Mitscher, Lester A.; Snutch, Terrance Preston
    We previously reported the small organic N-type calcium channel blocker NP078585 that while efficacious in animal models for pain, exhibited modest L-type calcium channel selectivity and substantial off-target inhibition against the hERG potassium channel. Structure-activity studies to optimize NP078585 preclinical properties resulted in compound 16, which maintained high potency for N-type calcium channel blockade, and possessed excellent selectivity over the hERG (~120-fold) and L-type (~3600-fold) channels. Compound 16 shows significant anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain and is also efficacious in the rat formalin model of inflammatory pain.
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    The Triggle effect
    (Elsevier, 2015-07-20) Snutch, Terrance Preston; Zamponi, Gerald W.
    Dr. David Triggle is considered a pioneer in the area of ion channel pharmacology. Over the course of his career, he made a number of particularly important contributions to our understanding of dihydropyridine interactions with L-type calcium channels. He also contributed his highly sought after expertise towards the drug discovery platform of the Canadian biopharmaceutical company, NeuroMed Pharmaceuticals (subsequently Zalicus). Here we briefly highlight his contributions to the field of calcium channel pharmacology, and then provide examples of his impact on NeuroMed.