Synergistic Multiresidue Substitutions of a Macrocyclic c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-dPro] Agouti-Related Protein (AGRP) Scaffold Yield Potent and >600-Fold MC4R versus MC3R Selective Melanocortin Receptor Antagonists.
Synergistic Multiresidue Substitutions of a Macrocyclic c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-dPro] Agouti-Related Protein (AGRP) Scaffold Yield Potent and >600-Fold MC4R versus MC3R Selective Melanocortin Receptor Antagonists.
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DOI：
10.1021/acs.jmedchem.8b00684
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发表时间：
2018-09-13
影响因子：
7.3
通讯作者：
Haskell-Luevano C
中科院分区：
文献类型：
--
作者：
Fleming KA;Freeman KT;Ericson MD;Haskell-Luevano C
黑皮质素-3和-4受体（MC 3R，MC 4 R）的拮抗剂配体，包括刺鼠相关蛋白（AGRP），被认为是治疗负能量平衡疾病的靶点。先前的研究报道了大环MC 3R/MC 4 R拮抗剂c[Pro 1-Arg 2-Phe 3-Phe 4-Asn 5-Ala 6-Phe 7-DPro 8]，其对小鼠（m）mMC 3R的效力比AGRP低250倍，对mMC 4 R的效力比AGRP低3倍。以前的研究探讨了这个模板中各个位置的结构-活性关系。在本文中，利用多残基取代策略，将前导序列与先前报道的hPhe 4、Dap 5、Arg 5、Ser 6和Nle 7取代组合。来自该研究的两种化合物（16，20）含有hPhe 4/Ser 6/Nle 7取代模式，对mMC 4 R的效力是AGRP的3-6倍，对mMC 4 R的选择性是mMC 3R的600-800倍。具有hPhe 4/Arg 5取代的另一种先导化合物（21）在mMC 3R处的效力仅比AGRP低5倍，并且在mMC 4 R处与AGRP等效。
Antagonist ligands of the melanocortin-3 and −4 receptors (MC3R, MC4R), including agouti-related protein (AGRP), are postulated to be targets for the treatment of diseases of negative energy balance. Previous studies reported the macrocyclic MC3R/MC4R antagonist c[Pro1−Arg2−Phe3−Phe4−Asn5−Ala6−Phe7−DPro8], which is 250-fold less potent at the mouse (m) mMC3R and 3-fold less potent at the mMC4R than AGRP. Previous studies explored the structure-activity relationships around individual positions in this template. Herein, a multiresidue substitution strategy is utilized, combining the lead sequence with hPhe4, Dap5, Arg5, Ser6, and Nle7 substitutions previously reported. Two compounds from this study (16, 20) contain an hPhe4/Ser6/Nle7 substitution pattern, are 3–6 fold more potent than AGRP at the mMC4R, and are 600–800 fold selective for the mMC4R over the mMC3R. Another lead compound (21), possessing the hPhe4/Arg5 substitutions, is only 5-fold less potent than AGRP at the mMC3R and is equipotent to AGRP at the mMC4R.
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DOI：
10.1006/bbrc.1993.2125
发表时间：
1993-09-15
影响因子：
3.1
作者：
CHHAJLANI, V;MUCENIECE, R;WIKBERG, JES
通讯作者：
WIKBERG, JES
影响因子：
5
作者：
Fleming KA;Ericson MD;Freeman KT;Adank DN;Lunzer MM;Wilber SL;Haskell-Luevano C
通讯作者：
Haskell-Luevano C
影响因子：
64.8
作者：
Fan, W;Boston, BA;Cone, RD
通讯作者：
Cone, RD
DOI：
10.3891/acta.chem.scand.33b-0763
发表时间：
1979-01-01
期刊：
ACTA CHEMICA SCANDINAVICA SERIES B-ORGANIC CHEMISTRY AND BIOCHEMISTRY
影响因子：
--
作者：
CHRISTENSEN, T
通讯作者：
CHRISTENSEN, T
DOI：
10.1006/bbrc.1994.1580
发表时间：
1994-05-16
影响因子：
3.1
作者：
GANTZ, I;SHIMOTO, Y;YAMADA, T
通讯作者：
YAMADA, T