Department of Cardiovascular Sciences, University of Leicester, Leicester Royal Infirmary, Leicester LE1 5WW, UK.
Br J Anaesth. 2012 Feb;108(2):262-70. doi: 10.1093/bja/aer377. Epub 2011 Dec 22.
While producing good-quality analgesia, µ-opioid (MOP) receptor activation produces a number of side-effects including tolerance. Simultaneous blockade of δ-opioid (DOP) receptors has been shown to reduce tolerance to morphine. Here, we characterize a prototype bifunctional opioid H-Dmt-Tic-Gly-NH-Bzl (UFP-505).
We measured receptor binding affinity in Chinese hamster ovary (CHO) cells expressing recombinant human MOP, DOP, k-opioid (KOP), nociceptin/orphanin (NOP) receptors. For activation, we measured the binding of GTPγ(35)S to membranes from CHO(hMOP), CHO(hDOP), rat cerebrocortex, and rat spinal cord. In addition, we assessed 'end organ' responses in the guinea pig ileum and mouse vas deferens.
UFP-505 bound to CHO(hMOP) and CHO(hDOP) with (binding affinity) pK(i) values of 7.79 and 9.82, respectively. There was a weak interaction at KOP and NOP (pK(i) 6.29 and 5.86). At CHO(hMOP), UFP-505 stimulated GTPγ(35)S binding with potency (pEC(50)) of 6.37 and in CHO(hDOP) reversed the effects of a DOP agonist with affinity (pK(b)) of 9.81 (in agreement with pK(i) at DOP). UFP-505 also stimulated GTPγ(35)S binding in rat cerebrocortex and spinal cord with pEC(50) values of 6.11-6.53. In the guinea pig ileum (MOP-rich preparation), UFP-505 inhibited contractility with pEC(50) of 7.50 and in the vas deferens (DOP-rich preparation) reversed the effects of a DOP agonist with an affinity (pA(2)) of 9.15.
We have shown in a range of preparations and assays that UFP-505 behaves as a potent MOP agonist and DOP antagonist; a MOP/DOP bifunctional opioid. Further studies in dual expression systems and whole animals with this prototype are warranted.
µ-阿片受体（MOP）激活除了产生良好的镇痛效果外，还会产生许多副作用，包括耐受。同时阻断 δ-阿片受体（DOP）已被证明可减少吗啡耐受。在这里，我们描述了一种原型双功能阿片类药物 H-Dmt-Tic-Gly-NH-Bzl（UFP-505）。
我们测量了在中国仓鼠卵巢（CHO）细胞中表达重组人 MOP、DOP、k-阿片受体（KOP）、孤啡肽/孤啡肽受体（NOP）的受体结合亲和力。对于激活，我们测量了 GTPγ（35）S 与 CHO（hMOP）、CHO（hDOP）、大鼠大脑皮层和大鼠脊髓膜的结合。此外，我们评估了豚鼠回肠和小鼠输精管中的“终末器官”反应。
UFP-505 与 CHO（hMOP）和 CHO（hDOP）的结合（结合亲和力）pK（i）值分别为 7.79 和 9.82。在 KOP 和 NOP 处存在弱相互作用（pK（i）为 6.29 和 5.86）。在 CHO（hMOP）中，UFP-505 以效力（pEC（50））6.37 刺激 GTPγ（35）S 结合，在 CHO（hDOP）中以亲和力（pK（b））9.81 逆转 DOP 激动剂的作用（与 DOP 处的 pK（i）一致）。UFP-505 还以 6.11-6.53 的 pEC（50）值刺激大鼠大脑皮层和脊髓的 GTPγ（35）S 结合。在富含 MOP 的豚鼠回肠（制剂）中，UFP-505 以 7.50 的 pEC（50）抑制收缩性，在富含 DOP 的输精管（制剂）中，以亲和力（pA（2））9.15 逆转 DOP 激动剂的作用。
我们在一系列制剂和测定中表明，UFP-505 作为一种有效的 MOP 激动剂和 DOP 拮抗剂；一种 MOP/DOP 双功能阿片类药物。在具有该原型的双表达系统和整体动物中进一步研究是必要的。
