Browsing by Author "Porreca, Frank"

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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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    Structure-activity relationships of diphenylpiperazine N-type calcium channel inhibitors
    (Elsevier Ltd., 2010-02-15) Pajouhesh, Hassan; Ding, Yanbing; Zhang, Lingyun; Pajouhesh, Hossein; Belardetti, Francesco; Simonson, Eric; Porreca, Frank; Mitscher, Lester A; Snutch, Terrance P; Feng, Zhong Ping; Morrison, Jerrie Lynn; Tringham, Elizabeth W.; Vanderah, Todd W.; Zamponi, Gerald W.
    A novel series of compounds derived from the previously reported N-type calcium channel blocker NP118809 (1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one) is described. Extensive SAR studies resulted in compounds with IC(50) values in the range of 10-150 nM and selectivity over the L-type channels up to nearly 1200-fold. Orally administered compounds 5 and 21 exhibited both anti-allodynic and anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain.
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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.