Ericson Mark D, Shaikh Romessa, Larson Courtney M, Freeman Katie T, Haskell-Luevano Carrie
Department of Medicinal Chemistry & Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, United States.
ACS Med Chem Lett. 2020 Dec 17;12(1):115-120. doi: 10.1021/acsmedchemlett.0c00561. eCollection 2021 Jan 14.
The five melanocortin receptors regulate numerous physiological functions. Although many ligands have been developed for the melanocortin-4 receptor (MC4R), the melanocortin-3 receptor (MC3R) has been less-well characterized, in part due to the lack of potent, selective tool compounds. Previously an Ac-His-Arg-(pI)DPhe-Tic-NH scaffold, inverting the Phe-Arg motif of the native melanocortin signal sequence, was identified to possess mMC3R over mMC4R selective agonist activity. In this study, a library of 12 compounds derived from this scaffold was synthesized and assayed at the mouse melanocortin receptors (MCRs), utilizing substitutions previously shown to increase mMC3R agonist potency and/or selectivity. One compound (, Ac-Val-Gln-DBip-DTic-NH) was identified as greater than 140-fold selective for the mMC3R over the mMC4R, possessed 70 nM potency at the mMC3R, and partially stimulated the mMC4R at 100 μM concentrations without antagonist activity. This pharmacological profile may be useful in developing new tool and therapeutic ligands that selective signal through the MC3R.
五种黑皮质素受体调节多种生理功能。尽管已经开发出许多针对黑皮质素-4受体（MC4R）的配体，但黑皮质素-3受体（MC3R）的特征描述较少，部分原因是缺乏强效、选择性的工具化合物。此前，一种Ac-His-Arg-(pI)DPhe-Tic-NH支架被发现具有相对于mMC4R的mMC3R选择性激动剂活性，该支架颠倒了天然黑皮质素信号序列的Phe-Arg基序。在本研究中，合成了一个由该支架衍生的12种化合物的文库，并在小鼠黑皮质素受体（MCRs）上进行了检测，利用先前显示可提高mMC3R激动剂效力和/或选择性的取代基。一种化合物（Ac-Val-Gln-DBip-DTic-NH）被确定对mMC3R的选择性比对mMC4R高140倍以上，在mMC3R上具有70 nM的效力，并且在100 μM浓度下部分刺激mMC4R而无拮抗剂活性。这种药理学特征可能有助于开发通过MC3R选择性信号传导的新工具和治疗性配体。
