Non-Peptide Somatostatin Agonist Analgesics

描述(申请人提供)：内源性生长抑素受体(SSTR)为通过外周和中枢机制治疗疼痛提供了新的靶点。我们的研究表明，外周SSTR的激活阻止了伤害性感受器的敏化，并提供了伤害性感受器的时相和紧张性抑制控制。这种调节是一个重要的治疗目标，因为炎症中外周伤害性感受器的敏化决定了原发性痛敏的性质和持续时间，并有助于中枢敏化和继发性痛敏。针对外周SSTR的临床研究进一步支持了全身应用SST肽类似物奥曲肽(OCT)后的止痛作用。以中枢SSTR为靶点治疗疼痛得到了20多年前的几项临床研究的支持。因此，鞘内注射天然SST和多肽类似物OCT可为剧烈疼痛(如癌症疼痛)提供止痛，即使在阿片类药物不再有效的情况下也是如此。不幸的是，由于现有的SST多肽药物对中枢神经系统的渗透性差，SST类似物通过中枢机制治疗疼痛的潜力尚未实现。我们的最终目标是开发被称为NISA(非肽咪唑烷二酮生长抑素激动剂)的非肽SSTR激动剂作为新型止痛药。第一阶段研究使用有效的和高度选择性的SSTR2 NISA，SCR007完成。在两种急性炎症模型中，通过局部(足底)或全身(IP)途径给予SCR007，可减少体内疼痛行为和体外伤害性感受器的外周敏化。在第二阶段，其他具有脂亲性的NISA类似物将被合成并在体外测试其抗伤害性特性(目标1)。SCR007和另一种有希望的NISA类似物(来自目标1)将在两种慢性疼痛模型(目标2和3)中进行测试，目的是识别一种适合于药物开发的止痛化合物。使用阿尔茨海默泵持续输注，候选药物的抗伤害效应将在2个临床相关的慢性疼痛模型中进行测试，这些模型含有炎症成分(脊髓损伤和完全弗氏佐剂诱导的疼痛)，通过2条途径(全身和鞘内)进行。我们将评估NISA治疗的行为、生理和解剖学结果，评估它们产生非常理想的止痛药的潜力，这些止痛药可以大大减少目前对阿片类药物的依赖。

DESCRIPTION (provided by applicant): Endogenous somatostatin receptors (SSTRs) offer novel targets for treating pain via both peripheral and central mechanisms. Our studies show that peripheral SSTR activation prevents nociceptor sensitization and provides phasic and tonic inhibitory control of nociceptors. This modulation is an important therapeutic goal since sensitization of peripheral nociceptors in inflammation defines the quality and duration of primary hyperalgesia and contributes to central sensitization and secondary hyperalgesia. Targeting peripheral SSTRs is further supported by clinical studies demonstrating analgesia following systemic administration of the SST peptide analog octreotide (OCT). The targeting of central SSTRs to treat pain is supported by several clinical studies that date back over 2 decades. Thus, intrathecal administration of native SST as well as the peptide analog OCT provides analgesia in severe pain (e.g. cancer pain) even in cases when opioids are no longer effective. Unfortunately, the potential of SST analogues for treating pain by central mechanisms has been unrealized due to poor CNS penetration of available SST peptide drugs. Our ultimate aim is to develop non-peptide SSTR agonists known as NISAs (Non-peptide Imidazolidinedione Somatostatin Agonists) as novel analgesics. Phase I studies were completed using the potent and highly SSTR2 selective NISA, SCR007. Administration of SCR007 by a local (intraplantar) or systemic (ip) route, reduced pain behaviors in vivo and peripheral sensitization of nociceptors in vitro in 2 models of acute inflammation. In Phase II, other NISA analogs with a spectrum of lipophilicities will be compounded and tested in vitro for antinociceptive properties (Aim 1). SCR007 and another promising NISA analogue (from Aim 1) will be tested in 2 models of chronic pain (Aims 2 and 3), with the aim of identifying an analgesic compound that is suitable for drug development. Using constant infusion by Alzet pumps, the anti-nociceptive effect of candidate drugs will be tested in 2 clinically relevant chronic pain models which have inflammatory components (spinal cord injury-and complete Freunds adjuvant-induced pain), via 2 routes (systemic and intrathecal). We will assess the behavioral, physiological and anatomical outcomes of NISAs treatment, evaluating their potential to yield highly desirable analgesics which could greatly reduce the current reliance on opioid therapies.