| Ion channels play a major role in the cellular signaling and control processes required within living systems. The voltage gated sodium channel (VGSC) belongs to this superfamily of ion channels and is known to have a critical function in electrically excitable cells, such as those found in neuronal, muscular and cardiac tissue. Ectopic firing of action potentials within neuronal systems can result in chronic pain syndromes, such as neuropathic pain. Therefore, VGSCs are central to the development of pain therapeutics.;Tricyclic antidepressants (TCAs), such as amitripyline, serve as the best treatment of neuropathic pain syndromes, to date and are thought to function by potently blocking sodium channel current. Although TCAs have wide therapeutic use, they do suffer from some adverse side effects which have led to patient withdrawal. We have therefore chosen to develop novel compounds from an amitriptyline scaffold, in order to obtain a more well tolerated and potent therapeutic. From our investigations, we have been able to identify two potent classes of amitriptyline analogues, which are di- and mono-phenyl amine. We have also determined that the tricyclic moiety is unnecessary for effective inhibition of both channel binding and sodium currents of hNa v1.2. Additionally, modification to the amine functionality has been found to be detrimental to block. Thus far, our most potent compound containing a monophenyl amine structure provides 94.6% functional block of sodium channels at 10 muM, which is a three-fold increase in current block in comparison to amitriptyline. Further evaluation of this analogue in animal models of inflammatory pain has shown promising results. |
