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 ( Drm SPR) 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 Drm SPR, 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 R 1 , R 2 , R 3 and R 4 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 Drm SPR with EC 50 values of 3–4 μM. [ABSTRACT FROM AUTHOR]