title: Discovery and structure-activity relationships of pyrazolodiazepine derivatives as the first small molecule agonists of the Drosophila sex peptide receptor.
abstract: In behavioral research, the sex peptide receptor in Drosophila melanogaster (DrmSPR) is the most interesting G protein-coupled receptor (GPCR) and is involved in post-mating responses such as increased egg-laying and decreased receptivity of the female; during these responses, the receptors are activated by a specific natural peptide agonist (sex peptide, SP). To discover small molecule agonists for DrmSPR, a compound library based on a pyrazolodiazepine scaffold, which was previously reported as a potential privileged structure, was screened. Structure-activity relationship (SAR) studies of the hit compounds, which exhibited weak agonistic effects (69-72% activation at 100μM), were explored through the synthesis of various analogs with substituents at the R1, R2, R3 and R4 positions of the pyrazolodiazepine skeleton. As a result, compounds 21 and 31 of the 6-benzyl pyrazolodiazepine derivative series were found to be small molecule agonists for DrmSPR with EC50 values of 3-4μM.
authors: School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea.
authors: Joeng-Hyun
authors: JH
authors: Kim
authors: Department of Medical System Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea.
authors: Pyeong-Hwa
authors: PH
authors: Jeong
authors: School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea.
authors: Ju-Yeon
authors: JY
authors: Lee
authors: School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea.
authors: Jae-Hyuk
authors: JH
authors: Lee
authors: School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea. Electronic address: kimyj@gist.ac.kr.
authors: Young-Joon
authors: YJ
authors: Kim
authors: School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea; Department of Medical System Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea. Electronic address: yongchul@gist.ac.kr.
authors: Yong-Chul
authors: YC
authors: Kim
mesh_terms: D000818:Animals; D001381:Azepines / Q000737:chemistry* / Q000494:pharmacology*; D004330:Drosophila / Q000187:drug effects / Q000502:physiology; D029721:Drosophila Proteins / Q000819:agonists* / Q000378:metabolism; D055808:Drug Discovery; D005260:Female; D008297:Male; D010455:Peptides / Q000819:agonists* / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D018000:Receptors, Peptide; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; D029721:Drosophila Proteins; D010455:Peptides; D011720:Pyrazoles; D018000:Receptors, Peptide; D054852:Small Molecule Libraries; C526291:sex peptide receptor, Drosophila
keywords: Agonist; Drosophila sex peptide receptor; G protein-coupled receptor; Pyrazolodiazepine; Structure–activity relationships