Novel cyclic templates of α-MSH give highly selective and potent antagonists/agonists for human melanocortin-3/4 receptors
Novel cyclic templates of α-MSH give highly selective and potent antagonists/agonists for human melanocortin-3/4 receptors
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DOI：
10.1021/jm020021z
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发表时间：
2002-06-06
影响因子：
7.3
通讯作者：
Hruby, VJ
中科院分区：
文献类型：
--
作者：
Kavarana, MJ;Trivedi, D;Hruby, VJ
为了开发高选择性和有效的hMC3和hMC4受体激动剂和/或拮抗剂，采用了一种新的方法，包括使用连接臂和主链到侧链的环化策略。三个关键的类似物被确定在hMC3或hMC4受体上具有所需的选择性和效力，暗示在能量平衡和其他生物效应中发挥关键作用。新的环肽(O)C-CH2-CH2-C(O)-C-[His(6)-D-Phe(7)-Arg-Trp(9)-Lys(10)]-NH2(1)被发现是一种高度选择性的hMC4受体激动剂。构效关系研究表明，用邻苯二甲酸基取代I的琥珀酰基连接臂，用D-NaL(2‘)(7)残基取代D-Phe(7)，可在hMC4受体上产生有效的拮抗剂7。此外，将1的23个内酰胺环增加一个碳原子(琥珀酸基-->；戊二酸连接物)，可以得到高度选择性和有效的hMC3受体拮抗剂9。因此，类似物1、7和9代表了一类环状促黑素配体的第一个例子，这些配体具有高选择性，并在生理上重要的hMC3和hMC4受体上具有明确的生物活性。
In an effort to develop highly selective and potent agonists and/or antagonists for the hMC3 and hMC4 receptors, a new approach involving the use of linker arms and a backbone to side chain cyclization strategy was employed. Three key analogues were identified to have the required selectivity and potency at the hMC3 or hMC4 receptors, implicated to play pivotal roles in energy homeostasis and other biological effects. The novel cyclic peptide (O)C-CH2-CH2-C(O)-C-[His(6)-D-Phe(7)-Arg-Trp(9)-Lys(10)]-NH2 (1) was found to be a highly selective and potent agonist of the hMC4 receptor. Structure-activity studies have shown that replacing the succinyl linker arm of I by an o-phthalic acid group and substituting a D-Nal(2')(7) residue in place of D-Phe(7) results in a potent antagonist 7 at the hMC4 receptor. Furthermore, increasing the 23-membered lactam ring of 1 by one carbon atom (succinyl --> glutaric acid linker) gives a highly selective and potent antagonist 9 for the hMC3 receptor. Analogues 1, 7, and 9 therefore represent the first examples of a class of cyclic melanotropin ligands with high selectivity and defined biological activities at the physiologically important hMC3 and hMC4 receptors.