Synthesis of Alpha2/Alpha3 GABA Agonists to Treat Neuropathic Pain

描述（由申请人提供）：神经性疼痛包括一系列不同起源的疼痛状况，包括糖尿病性神经病变、疱疹后神经痛和手术后神经损伤。它包括截瘫后的疼痛，对非疼痛性刺激的超敏反应（异常性疼痛），例如手术后或偏头痛发作期间，自发性疼痛，痛觉过敏和肌面综合征的弥漫性肌肉压痛。背痛、癌症疼痛和艾滋病相关疼痛也属于神经性疼痛。目前用于神经性疼痛的处方药物通常是成瘾性的，不是对所有患者有效，并且具有各种副作用，包括耐受性、成瘾性、镇静、肝毒性。仅在美国，生产力下降带来的经济负担就高达数十亿美元，尽管这些患者遭受着痛苦。最近，我们发现了一系列非镇静性α 2/α 3 BzR/GABA（A）激动剂，它们对神经性疼痛以及焦虑症和惊厥具有活性。这些药物不会产生耐受性，并且由特权支架（咪唑并苯并二氮杂卓）组成，其结果是毒性机会较小。因为它们对a1和a5亚型表现出很少或没有功效，所以它们将表现出很少或没有滥用潜力。本研究集中于这些新药物的修饰，以延长体内作用的持续时间，并在α 2或α 3 BzR/GABA（A）能亚型上提供更好的亚型选择性。这将排除副作用的来源，包括镇静、共济失调、健忘、耐受和滥用的可能性。此外，这项工作将有助于确定脊髓中哪种GABaerigc亚型是选择的伤害性靶点。最终的目标是用这些更安全、非成瘾性的配体取代成瘾性阿片类镇痛药，用于治疗人群中所有类型的神经性疼痛和炎性疼痛。

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.