Substrate-selective inhibition of COX-2 to target affective disorders

描述（由申请人提供）：情绪和焦虑障碍给患者和家庭带来了巨大的社会成本和个人负担。目前这些疾病的治疗方法主要集中在增加脑神经递质，如血清素，即通过选择性降钙素再摄取抑制剂（SSRI）。然而，大规模的有效性研究表明，这类药物只是部分有效。最近的研究表明，提高内源性大脑大麻素的水平可以对情绪和焦虑症（包括创伤后应激障碍）产生治疗益处。我们最近开发了新的环氧合酶-2（考克斯-2）抑制剂，其选择性地防止脑内源性大麻素的失活，而不阻止异黄酮的合成;异黄酮是正常免疫和血管功能所需的炎症介质。考虑到前列腺素合成的长期抑制与胃肠道和心血管毒性相关，开发、验证和临床前评价调节考克斯-2活性以增强内源性大麻素信号传导而不影响前列腺素合成的新型药理学策略是一项高度优先的研究。我们将检验以下假设：考克斯-2的“底物选择性”抑制剂选择性地增加脑内源性大麻素水平而不影响前列腺素水平，并且它们在情绪和焦虑障碍模型中发挥临床前功效。这些研究的完成将为一类新型抗抑郁和抗焦虑药物的疗效提供临床前证据，并可以验证考克斯-2作为未来针对情感障碍治疗的药物发现的可行分子靶点。

DESCRIPTION (provided by applicant): Mood and anxiety disorders exert substantial societal cost and personal burden for patients and families. Current treatment approaches for these disorders are primarily focused on increasing brain neurotransmitters like serotonin, i.e. via selective serotonin-reuptake inhibitors (SSRIs). However, large-scale effectiveness studies have demonstrated this class of drugs is only partially effective. Recent studies have suggested that elevating levels of endogenous brain cannabinoids could exert therapeutic benefit in mood and anxiety disorders including PTSD. We have recently developed novel inhibitors of cyclooxygenase-2 (COX-2) that selectively prevent inactivation of brain endocannabinoids without preventing synthesis of prostaglandins; which are inflammatory mediators required for normal immune and vascular function. Given that long-term inhibition of prostaglandin synthesis is associated with gastrointestinal and cardiovascular toxicity, development, validation, and preclinical evaluation of novel pharmacological strategies to modulate COX-2 activity to enhance endocannabinoid signaling without affecting prostaglandin synthesis is a high research priority. We will test the hypothesis that "substrate-selective" inhibitors of COX-2 selectively increase brain endocannabinoid levels without affecting prostaglandin levels and that they exert preclinical efficacy in models of mood and anxiety disorders. Completion of these studies will provide preclinical evidence for the efficacy of a novel class of antidepressant and anxiolytic drugs, and could validate COX-2 as a viable molecular target for future drug discovery directed at the treatment of affective disorders.