Agnes Richard S, Lee Yeon Sun, Davis Peg, Ma Shou-Wu, Badghisi Hamid, Porreca Frank, Lai Josephine, Hruby Victor J
Departments of Chemistry and Pharmacology, University of Arizona, Tucson, Arizona 85721, USA.
J Med Chem. 2006 May 18;49(10):2868-75. doi: 10.1021/jm050921q.
Cholecystokinin (CCK) has been identified as a pronociceptive endogenous peptide which also possesses antiopioid actions. CCK may be upregulated in conditions of chronic pain or during sustained morphine administration resulting in attenuation of opioid-mediated pain relief. These complex interactions between opioids and endogenous CCK receptor systems have suggested the need for a new paradigm in drug design for some states of chronic pain. In these circumstances the rational design of potential drugs for the treatment of these conditions must be based on one ligand for multiple targets. We have designed a single peptide which can interact with delta and mu opioid receptors as agonists and with CCK receptors as antagonists. The ligands were designed based on a model of overlapping pharmacophores of opioid and CCK peptide ligands, which incorporates opioid pharmacophores at the N-terminal and CCK tetrapeptide pharmacophores at the C-terminal of the designed ligands. We measured binding and activities of our bifunctional peptides at opioid and CCK receptors. Compound 11 (Tyr-d-Ala-Gly-d-Trp-NMeNle-Asp-Phe-NH(2)) demonstrated opioid agonist properties at delta and mu receptors (IC(50) = 63 +/- 27 nM and 150 +/- 65 nM, respectively in MVD and GPI tissue assays) and high binding affinity at CCK-1 and CCK-2 receptors (K(i) = 320 and 1.5 nM, respectively). Compound 9 (Tyr-d-Nle-Gly-Trp-Nle-Asp-Phe-NH(2)) displayed potent agonist activity at delta and mu receptors (IC(50) = 23 +/-10 nM and 210 +/- 52 nM, respectively in MVD and GPI tissue assays), with a balanced binding affinity for CCK-1 and CCK-2 receptors (K(i) = 9.6 and 15 nM, respectively). These results provide evidence supporting the concept that opioid and CCK receptors have overlapping pharmacophores required for binding affinity and biological activity and that designing overlapping pharmacophores of two peptides into a single peptide is a valid drug design approach.
胆囊收缩素（CCK）已被确认为一种促伤害感受的内源性肽，它还具有抗阿片样物质的作用。在慢性疼痛状态下或持续给予吗啡期间，CCK可能会上调，导致阿片类药物介导的疼痛缓解作用减弱。阿片类药物与内源性CCK受体系统之间的这些复杂相互作用表明，对于某些慢性疼痛状态，需要一种新的药物设计范式。在这种情况下，用于治疗这些病症的潜在药物的合理设计必须基于一种针对多个靶点的配体。我们设计了一种单一肽，它可以作为激动剂与δ和μ阿片受体相互作用，并作为拮抗剂与CCK受体相互作用。这些配体是基于阿片肽和CCK肽配体的重叠药效团模型设计的，该模型在设计配体的N端包含阿片药效团，在C端包含CCK四肽药效团。我们测量了双功能肽在阿片受体和CCK受体上的结合和活性。化合物11（Tyr-d-Ala-Gly-d-Trp-NMeNle-Asp-Phe-NH(2)）在δ和μ受体上表现出阿片激动剂特性（在MVD和GPI组织测定中，IC(50)分别为63±27 nM和150±65 nM），并且在CCK-1和CCK-2受体上具有高结合亲和力（K(i)分别为320和1.5 nM）。化合物9（Tyr-d-Nle-Gly-Trp-Nle-Asp-Phe-NH(2)）在δ和μ受体上表现出强效激动剂活性（在MVD和GPI组织测定中，IC(50)分别为23±10 nM和210±52 nM），对CCK-1和CCK-2受体具有平衡的结合亲和力（K(i)分别为9.6和15 nM）。这些结果提供了证据，支持以下概念：阿片受体和CCK受体具有重叠的药效团，这些药效团是结合亲和力和生物活性所必需的，并且将两种肽的重叠药效团设计到一种单一肽中是一种有效的药物设计方法。
