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

Bioorg Med Chem. 2015 Apr 15;23(8):1808-16. doi: 10.1016/j.bmc.2015.02.035. Epub 2015 Feb 24.

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.

Keywords: Agonist; Drosophila sex peptide receptor; G protein-coupled receptor; Pyrazolodiazepine; Structure–activity relationships.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azepines / chemistry*
  • Azepines / pharmacology*
  • Drosophila / drug effects
  • Drosophila / physiology
  • Drosophila Proteins / agonists*
  • Drosophila Proteins / metabolism
  • Drug Discovery
  • Female
  • Male
  • Peptides / agonists*
  • Peptides / metabolism
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacology*
  • Receptors, Peptide
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • Azepines
  • Drosophila Proteins
  • Peptides
  • Pyrazoles
  • Receptors, Peptide
  • Small Molecule Libraries
  • sex peptide receptor, Drosophila