Discovery and structure–activity relationships of pyrazolodiazepine derivatives as the first small molecule agonists of the Drosophila sex peptide receptor

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 100 μM), 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 3–4 μM.

CompoundR3% Act (100 μM)EC50 (μM)3–CO(CH2)2(C5H9)72—21–CO(CH2)2(C5H9)2953.931–CO(CH2)3CH33213.2Full-size tableTable optionsView in workspaceDownload as CSVFigure optionsDownload as PowerPoint slide