Pyrazolodiazepine derivatives with agonist activity toward Drosophila RYamide receptor

[Display omitted] •Drosophila RYa-R is an ortholog of mammalian NPYRs, metabolic diseases targets.•Specific agonists of RYa-R were screened from pyrazolodiazepine analog library.•A core structure is phenylalanine and lysine fused pyrazolodiazepine skeletons.•A lead compound structure for the drug de...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2016-10, Vol.26 (20), p.5116-5118
Main Authors: Yoon, Yeu Kyung, Kim, Jung Ha, Kim, Jeong-hyun, Kwon, Jae-Young, Kim, Yong-Chul, Kim, Young-Joon, Park, Zee-Yong
Format: Article
Language:English
Subjects:
Agonist
Animals
Drosophila
Drug Design
GPCR
Neuropeptide Y receptor
Pyrazoles - pharmacology
Pyrazolodiazepine
Receptors, Neuropeptide - agonists
RYamide receptor
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Summary:[Display omitted] •Drosophila RYa-R is an ortholog of mammalian NPYRs, metabolic diseases targets.•Specific agonists of RYa-R were screened from pyrazolodiazepine analog library.•A core structure is phenylalanine and lysine fused pyrazolodiazepine skeletons.•A lead compound structure for the drug development of mammalian NPYRs is provided. The neuropeptide Y (NPY)-like signaling is conserved broadly in many animal species, and implicated in diverse biological functions, particularly those associated with feeding and metabolism. In Drosophila, three G protein coupled receptors (GPCRs) are closely related to the vertebrate NPY receptors: RYamide receptor (RYa-R) CG5811, neuropeptide F receptor (NPFR) CG1147 and short neuropeptide F receptor (sNPF-R) CG7395. Here, we screened 442 compounds of the pyrazolodiazepine analogs library, and identified four synthetic small compounds that activate the RYa-R, but not other two receptors. Their maximum activity is about 40% of the endogenous ligand, Drosophila RYamide-1, indicating they are partial agonists. Structural comparisons of these agonists identified an active core structure, characterized by phenylalanine and lysine fused pyrazolodiazepine skeletons, which can be utilized as a lead structure for further development of more potent drugs active on mammalian NPYRs. Identification of small compound agonists selective on RYa-R of the genetically amenable insect model will facilitate future efforts to understand biological functions of RYa-R, a GPCR conserved in many species.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2016.08.039