Synthesis of Alpha2/Alpha3 GABA Agonists to Treat Neuropathic Pain

$318,422R01FY2015NSNIH

University Of Wisconsin Milwaukee, Milwaukee WI

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Abstract

DESCRIPTION (provided by applicant): Neuropathic pain encompasses a range of painful conditions of diverse origins including diabetic neuropathy, post-herpetic neuralgia and nerve injuries after surgery. It includes pain following paraplegia, hypersensitivity to non-painful stimli (allodynia), for example after surgery or during migraine attacks, spontaneous pain, hyperalgesia and diffuse muscle tenderness of myofacial syndromes. Back pain, cancer pain and AIDS associated pain also qualify as neuropathic pain. Currently prescribed drugs for neuropathic pain are often addictive, are not effective for all patients and have various side effects including tolerance, addiction, sedation, liver toxicity. The financial burden from the los of productivity in the US alone numbers in the billions of dollars notwithstanding the misery these patients suffer. Recently, we have discovered a series of nonsedating alpha2/alpha3 BzR/GABA (A) agonists that are active against neuropathic pain as well as anxiety disorders and convulsions. These agents do not develop tolerance and are comprised of a privileged scaffold (imidazobenzodiazepine), the result of which has less chance for toxicity. Because they exhibit little or no efficacy at a1 and a5 subtypes, they will exhibit very little or no abuse potential. This research centers on the modification of these new agents to prolong duration of action in vivo and to provide better subtype selectivity at either a2 or a3 BzR/GABA(A)ergic subtypes. This would preclude the origin of side effects including sedation, ataxia, amnesia, tolerance and abuse potential. In addition, this work will help to establish which GABAerigc subtype in the spinal cord is the nociceptive target of choice. An eventual goal is to replace the addictive opioid analgesics with these safer, non addictive ligands for treatment of all types of neuropathic and inflammatory pain, in human populations.

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