Abstract| Volume 14, ISSUE 4, SUPPLEMENT , S71, April 2013

Z160: A potent and state-dependent, small molecule blocker of N-type calcium channels effective in nonclinical models of neuropathic pain

      N-type voltage-gated calcium channels are validated targets for chronic and neuropathic pain, yet the only approved pharmacological agent that directly modulates this target demonstrates significant limitations. Ziconotide potently blocks the channel, but lack of selectivity for nociceptive N-type channels, including effects on peripheral N-type channels that regulate the cardiovascular system, results in severe side effects when administered systemically. Gabapentin and pregabalin, through interaction with the channel alpha-2-delta subunit, are thought to reduce the number and function of calcium channels at synaptic terminals. While this mechanism is better tolerated in humans, it has a slow onset of action, limited responder rates and side effects such as somnolence and sedation, possibly associated with nonspecific effects on calcium channel subtypes or lack of state-dependent effects. These limitations have driven the discovery and development of Z160, a potent, selective, state-dependent, small molecule N-type calcium channel blocker. Z160 blocked native and recombinant N-type channel currents in an irreversible, dose-dependent manner with sub-micromolar potency and 25- to 100-fold selectivity over P/Q- and L-type calcium channels. Z160 mediated a hyperpolarizing shift in steady-state inactivation, consistent with a mechanism involving inactivated state blockade. Z160 also demonstrated use-dependent block of N-type channels, with significantly greater potency at stimulation frequencies similar to the action potential firing rate typical of neurons processing pain signals. After oral administration in the Chung and CCI rodent models of neuropathic pain, Z160 demonstrated dose-dependent reduction of thermal hyperalgesia and tactile allodynia at levels comparable to morphine, ω-conotoxin MVIIA and gabapentin with no motor effects as measured by rotarod. These data demonstrate that Z160 is a novel, potent, selective and state-dependent N-type channel blocker with efficacy in animal models of neuropathic pain. The attractive nonclinical profile of Z160 supports further investigation in human clinical trials of neuropathic pain. Supported by Zalicus Pharmaceuticals LTD.