Structure-Activity Relationship Studies of a Macrocyclic AGRP-Mimetic Scaffold c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro] Yield Potent and Selective Melanocortin-4 Receptor Antagonists and Melanocortin-5 Receptor Inverse Agonists That Increase Food Intake in Mice.
Structure-Activity Relationship Studies of a Macrocyclic AGRP-Mimetic Scaffold c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro] Yield Potent and Selective Melanocortin-4 Receptor Antagonists and Melanocortin-5 Receptor Inverse Agonists That Increase Food Intake in Mice.
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DOI：
10.1021/acschemneuro.7b00495
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发表时间：
2018-05-16
影响因子：
5
通讯作者：
Haskell-Luevano C
中科院分区：
文献类型：
--
作者：
Fleming KA;Ericson MD;Freeman KT;Adank DN;Lunzer MM;Wilber SL;Haskell-Luevano C
The melanocortin system has five receptors and antagonists of the central melanocortin receptors (MC3R, MC4R) are postulated to be viable therapeutics for disorders of negative energy balance such as anorexia, cachexia, and failure to thrive. Agouti-related protein (AGRP) is an antagonist of the MC3R and an antagonist/inverse agonist of the MC4R. Biophysical NMR based structural studies have demonstrated that the active sequence of this hormone, Arg-Phe-Phe, is located on an exposed β-hairpin loop. It has previously been demonstrated that the macrocyclic octapeptide scaffold c[Pro1-Arg2-Phe3-Phe4-Asn5-Ala6-Phe7-DPro8] is 16-fold less potent than AGRP at the mMC4R. Herein, it was hypothesized that the Phe7 position may be substituted to produce more potent and/or selective melanocortin receptor antagonist ligands based on this template. A ten-member library was synthesized that substituted small (Gly), polar (Ser), acidic (Asp), basic (Lys), aliphatic (Leu, Nle, and Cha), and aromatic (Trp, Tyr, hPhe) amino acids to explore potential modifications at the Phe7 position. The most potent mMC4R antagonist contained a Nle7 substitution, was equipotent to the lead ligand, 200-fold selective for the mMC4R over the mMC3R, and caused a significant increase in food intake when injected intrathecally (i.t.) into male mice. Three compounds possessed sigmoidal dose-response inverse agonist curves at the mMC5R, while the remaining seven decreased cAMP production from basal levels at 100 μM concentrations. These findings will add to the knowledge base towards the development of potent and selective probes to study the role of the melanocortin system in diseases of negative energy balance, and can be useful in the design of molecular probes to examine the physiological functions of the mMC5R.
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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：
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
DOI：
10.1006/bbrc.1994.1550
发表时间：
1994-04-29
影响因子：
3.1
作者：
GRIFFON, N;MIGNON, V;SOKOLOFF, P
通讯作者：
SOKOLOFF, P