Pyrazolodiazepine derivatives with agonist activity toward Drosophila RYamide receptor.
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.
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
Yeu Kyung
YK
Yoon
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
Jung Ha
JH
Kim
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
Jeong-Hyun
JH
Kim
Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Republic of Korea.
Jae-Young
JY
Kwon
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
Yong-Chul
YC
Kim
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
Young-Joon
YJ
Kim
School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea. Electronic address: zeeyong@gist.ac.kr.
Zee-Yong
ZY
Park
D000818:Animals; D004330:Drosophila; D015195:Drug Design; D011720:Pyrazoles / Q000494:pharmacology*; D018013:Receptors, Neuropeptide / Q000819:agonists*
D011720:Pyrazoles; D018013:Receptors, Neuropeptide
Agonist; GPCR; Neuropeptide Y receptor; Pyrazolodiazepine; RYamide receptor