Deekonda Srinivas, Rankin David, Davis Peg, Lai Josephine, Porreca Frank, Hruby Victor J
Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA.
Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA.
Bioorg Med Chem Lett. 2015 Oct 1;25(19):4148-52. doi: 10.1016/j.bmcl.2015.08.014. Epub 2015 Aug 14.
We report here the design and synthesis of novel multifunctional ligands that act as (μ/δ) opioid agonists and bradykinin 2 receptor antagonists. These multifunctional ligands were designed to interact with the multiple receptors to show an enhanced analgesic effect, with no opioid-induced tolerance. We designed our multifunctional ligands based on the well-known second generation bradykinin 2 receptor antagonist Hoe 140 (DArg-Arg-Pro-Hyp-Gly-Thi-Ser-DTic-Oic-Arg-OH) and the opioid enkephalin analogues Tyr-DAla-Phe, Tyr-DAla-Gly-Phe and Tyr-Pro-Phe. We explored the conjugation of opioid pharmacophore to the Hoe 140 (DArg-Arg-Pro-Hyp-Gly-Thi-Ser-DTic-Oic-Arg-OH) in various positions with and without a linker. These bifunctional ligands showed very good binding affinity towards the both μ and δ opioid receptors. Among these bifunctional ligands 8, 11 and 12 showed excellent and balanced binding affinity at both μ and δ opioid receptors (0.5 nM, 2.0 nM; 0.3 nM, 2 nM; 2 nM and 3 nM), respectively. On the other hand these bifunctional ligands showed very weak and no binding affinity for rat brain bradykinin 2 receptors. Similarly, the Hoe 140 showed very low affinity (>10,000 nM and 9,000 nM) against [(3)H] BK binding in rat brain membranes and in HEK293 cells, respectively. In contrast, the Hoe 140 showed very good binding affinity in guinea pig ileum (0.43 nM) similar to that of previously reported. The bradykinin 2 receptors are known to be present in rat brain membrane, guinea pig ileum (GPI) and rabbit jugular vein. Previously the binding affinity of Hoe 140 for bradykinin 2 receptor was reported using guinea pig ileum. The above results suggest that the bradykinin 2 receptors present in rat brain membrane are a different sub type than the bradykinin 2 receptor present in guinea pig ileum (GPI).
我们在此报告新型多功能配体的设计与合成，这些配体兼具（μ/δ）阿片样物质激动剂和缓激肽2受体拮抗剂的作用。设计这些多功能配体是为了使其与多种受体相互作用，以展现增强的镇痛效果，且无阿片类药物诱导的耐受性。我们基于著名的第二代缓激肽2受体拮抗剂Hoe 140（DArg-Arg-Pro-Hyp-Gly-Thi-Ser-DTic-Oic-Arg-OH）以及阿片脑啡肽类似物Tyr-DAla-Phe、Tyr-DAla-Gly-Phe和Tyr-Pro-Phe来设计我们的多功能配体。我们探索了在有或没有连接子的情况下，阿片药效基团在Hoe 140（DArg-Arg-Pro-Hyp-Gly-Thi-Ser-DTic-Oic-Arg-OH）的不同位置上的缀合。这些双功能配体对μ和δ阿片受体均表现出非常好的结合亲和力。在这些双功能配体中，8、11和12分别在μ和δ阿片受体上表现出优异且平衡的结合亲和力（0.5 nM，2.0 nM；0.3 nM，2 nM；2 nM和3 nM）。另一方面，这些双功能配体对大鼠脑缓激肽2受体表现出非常弱的结合亲和力或无结合亲和力。同样，Hoe 140分别对大鼠脑膜和HEK293细胞中的[³H]BK结合显示出非常低的亲和力（>10,000 nM和9,000 nM）。相比之下，Hoe 140在豚鼠回肠中表现出非常好的结合亲和力（0.43 nM），与先前报道的相似。已知缓激肽2受体存在于大鼠脑膜、豚鼠回肠（GPI）和兔颈静脉中。先前使用豚鼠回肠报道了Hoe 140对缓激肽2受体的结合亲和力。上述结果表明，大鼠脑膜中存在的缓激肽2受体与豚鼠回肠（GPI）中存在的缓激肽2受体是不同的亚型。
