Abstract
The melanocortin system consists of five seven-transmembrane spanning G-protein coupled receptors (MC1-5) that are stimulated by endogenous agonists and antagonized by the only two known endogenous antagonists of GPCRs, agouti and agouti-related protein (AGRP). These receptors have been associated with many physiological functions, including the involvement of the MC4R in feeding behavior and energy homeostasis, making this system an attractive target for the treatment of obesity. Small-molecule mimetics of endogenous ligands may result in the development of compounds with properties more suitable for use as therapeutic agents. The research presented herein involves the synthesis and analysis of 12 melanocortin receptor agonists using the 1,4-benzodiazepine-2,5- dione template and is the first report of these derivatives as melanocortin receptor agonists. Structure-activity relationship studies using this privileged structure template has resulted in molecules with molecular weights around 400 that possess nanomolar agonist potency at the melanocortin receptors examined in this study.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1423-1431 |
| Number of pages | 9 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 51 |
| Issue number | 5 |
| DOIs | |
| State | Published - Mar 13 2008 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Organic Chemistry
Cite this
The 1,4-benzodiazepine-2,5-dione small molecule template results in melanocortin receptor agonists with nanomolar potencies. / Joseph, Christine G.; Wilson, Krista R.; Wood, Michael S.; Sorenson, Nicholas B.; Phan, Dong V.; Xiang, Zhimin; Witek, Rachel M.; Haskell-Luevano, Carrie.
In: Journal of Medicinal Chemistry, Vol. 51, No. 5, 13.03.2008, p. 1423-1431.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The 1,4-benzodiazepine-2,5-dione small molecule template results in melanocortin receptor agonists with nanomolar potencies
AU - Joseph, Christine G.
AU - Wilson, Krista R.
AU - Wood, Michael S.
AU - Sorenson, Nicholas B.
AU - Phan, Dong V.
AU - Xiang, Zhimin
AU - Witek, Rachel M.
AU - Haskell-Luevano, Carrie
PY - 2008/3/13
Y1 - 2008/3/13
N2 - The melanocortin system consists of five seven-transmembrane spanning G-protein coupled receptors (MC1-5) that are stimulated by endogenous agonists and antagonized by the only two known endogenous antagonists of GPCRs, agouti and agouti-related protein (AGRP). These receptors have been associated with many physiological functions, including the involvement of the MC4R in feeding behavior and energy homeostasis, making this system an attractive target for the treatment of obesity. Small-molecule mimetics of endogenous ligands may result in the development of compounds with properties more suitable for use as therapeutic agents. The research presented herein involves the synthesis and analysis of 12 melanocortin receptor agonists using the 1,4-benzodiazepine-2,5- dione template and is the first report of these derivatives as melanocortin receptor agonists. Structure-activity relationship studies using this privileged structure template has resulted in molecules with molecular weights around 400 that possess nanomolar agonist potency at the melanocortin receptors examined in this study.
AB - The melanocortin system consists of five seven-transmembrane spanning G-protein coupled receptors (MC1-5) that are stimulated by endogenous agonists and antagonized by the only two known endogenous antagonists of GPCRs, agouti and agouti-related protein (AGRP). These receptors have been associated with many physiological functions, including the involvement of the MC4R in feeding behavior and energy homeostasis, making this system an attractive target for the treatment of obesity. Small-molecule mimetics of endogenous ligands may result in the development of compounds with properties more suitable for use as therapeutic agents. The research presented herein involves the synthesis and analysis of 12 melanocortin receptor agonists using the 1,4-benzodiazepine-2,5- dione template and is the first report of these derivatives as melanocortin receptor agonists. Structure-activity relationship studies using this privileged structure template has resulted in molecules with molecular weights around 400 that possess nanomolar agonist potency at the melanocortin receptors examined in this study.
UR - http://www.scopus.com/inward/record.url?scp=41649108801&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=41649108801&partnerID=8YFLogxK
U2 - 10.1021/jm701303z
DO - 10.1021/jm701303z
M3 - Article
C2 - 18271518
AN - SCOPUS:41649108801
VL - 51
SP - 1423
EP - 1431
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 5
ER -