Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland.
Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, P.O. Box 66, 00014, Helsinki, Finland.
ChemMedChem. 2019 May 6;14(9):965-981. doi: 10.1002/cmdc.201900074. Epub 2019 Apr 2.
We previously demonstrated the potential of di- or trisubstituted azulenes as ligands (potentiators, weak agonists, and antagonists) of the orexin receptors. In this study we investigated 27 1-benzoylazulene derivatives, uncovering seven potentiators of the orexin response on OX and two weak dual orexin receptor agonists. For potentiators, replacement of the azulene scaffold by indole retained the activity of four out of six compounds. The structure-activity relationships for agonism and potentiation can be summarized into a bicyclic aromatic ring system substituted with two hydrogen-bond acceptors (1-position, benzoyl; 6-position, carboxyl/ester) within 7-8 Å of each other; a third acceptor at the 3-position is also well tolerated. The same pharmacophoric signature is found in the preferred conformations of the orexin receptor agonist Nag26 from molecular dynamics simulations. Subtle changes switch the activity between weak agonism and potentiation, suggesting overlapping binding sites.
我们之前证明了二取代或三取代氮蒽类化合物作为食欲素受体配体（增效剂、弱激动剂和拮抗剂）的潜力。在这项研究中，我们研究了 27 种 1-苯甲酰氮蒽衍生物，发现了 7 种对 OX 有增效作用的食欲素反应增强剂和 2 种弱双重食欲素受体激动剂。对于增效剂，氮蒽骨架被吲哚取代后，其中 6 种化合物中有 4 种仍具有活性。激动作用和增效作用的构效关系可以概括为一个双环芳香环系统，在彼此相距 7-8Å 的位置上用两个氢键受体（1 位，苯甲酰基；6 位，羧基/酯基）取代；第三个受体在 3 位也能很好地耐受。在分子动力学模拟中，食欲素受体激动剂 Nag26 的首选构象也发现了相同的药效团特征。细微的变化将活性从弱激动作用切换为增效作用，表明存在重叠的结合位点。
