Non-Peptide Somatostatin Agonist Analgesics

描述（由申请人提供）：内源性生长抑素受体（SSTR）提供了通过外周和中枢机制治疗疼痛的新靶点。我们的研究表明，外周SSTR激活防止伤害感受器敏化，并提供伤害感受器的阶段性和紧张性抑制控制。这种调节是一个重要的治疗目标，因为炎症中外周伤害感受器的致敏决定了原发性痛觉过敏的质量和持续时间，并有助于中枢致敏和继发性痛觉过敏。靶向外周SSTR进一步得到了临床研究的支持，这些临床研究证明了SST肽类似物奥曲肽（OCT）全身给药后的镇痛作用。靶向中枢SSTR治疗疼痛得到了几项临床研究的支持，这些研究可以追溯到20多年前。因此，鞘内施用天然SST以及肽类似物OCT在重度疼痛（例如癌症疼痛）中提供镇痛，即使在阿片类药物不再有效的情况下。不幸的是，SST类似物通过中枢机制治疗疼痛的潜力尚未实现，这是由于可用SST肽药物的CNS渗透性差。我们的最终目标是开发非肽SSTR激动剂，称为NISA（非肽咪唑烷二酮生长抑素激动剂）作为新型镇痛药。使用强效且高度SSTR 2选择性的NISA（SCR 007）完成了I期研究。在2种急性炎症模型中，通过局部（足底内）或全身（ip）途径施用SCR007，减少了体内疼痛行为和体外伤害感受器的外周致敏。在II期，将合成具有一系列亲脂性的其他NISA类似物，并在体外测试其抗伤害感受特性（目的1）。SCR007和另一种有前途的NISA类似物（来自目标1）将在2种慢性疼痛模型（目标2和3）中进行测试，目的是鉴定适合药物开发的镇痛化合物。通过Alzet泵持续输注，将在2种具有炎症成分的临床相关慢性疼痛模型（脊髓损伤和完全弗氏镇痛剂诱导的疼痛）中通过2种途径（全身和鞘内）测试候选药物的抗伤害性作用。我们将评估NISAs治疗的行为，生理和解剖结果，评估其产生非常理想的镇痛药的潜力，这可以大大减少目前对阿片类药物治疗的依赖。

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.