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  3. Identification of novel β-lactams and pyrrolidinone derivatives as selective Histamine-3 receptor (H3R) modulators as possible anti-obesity agents

Identification of novel β-lactams and pyrrolidinone derivatives as selective Histamine-3 receptor (H3R) modulators as possible anti-obesity agents

  • Eur J Med Chem. 2018 May 25;152:148-159. doi: 10.1016/j.ejmech.2018.04.020.
Anirban Ghoshal 1,  Ajeet Kumar 2,  Doddapaneni Yugandhar 3,  Chandan Sona 4,  Sunu Kuriakose 5,  Kommu Nagesh 5,  Mamunur Rashid 6,  Sandeep K Singh 7,  Muhammad Wahajuddin 7,  Prem N Yadav 8,  Ajay K Srivastava 9
Affiliations

Affiliations

  • 1 Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, 226031, India.
  • 2 Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
  • 3 Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110025, India; Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India.
  • 4 Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110025, India.
  • 5 Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India.
  • 6 Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
  • 7 Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110025, India.
  • 8 Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110025, India. Electronic address: pn.yadav@cdri.res.in.
  • 9 Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110025, India; Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India. Electronic address: ajayk.srivastava@cdri.res.in.
PMID: 29704723 DOI: 10.1016/j.ejmech.2018.04.020
Abstract

Four series of structurally related β-lactams, 2,5-pyrrolidinediones, azaspirodecatrienediones (ASDT) and dihydropyrroloquinoxalinetriones (DPQT) were synthesized by utilizing post-Ugi modifications in one-pot, and their activity towards human histamine-3 receptor (H3R) was evaluated. Out of 94 compounds, screened against histamine-3 receptor (H3R), 21 compounds showed high H3R selective agonist property with EC50 values ranging from 187 nM to 0.1 nM, whereas none of the compound was found to have the affinity towards other receptors of histamine family such as histamine H1, H2, and H4 receptor. All active compounds have no assay interference activity as determined by in-silico analysis and receptor independent luciferase assay and cell cytotoxicity assay. Given the important role of H3R in hypophagia, we also evaluated the in vivo effect of the representative compound 6k on the cumulative food intake in diet induce obese C57BL6/J mice. Interestingly, we observed that single dose administration (20 mg/kg, intraperitoneal injection) of 6k significantly suppressed cumulative food intake, while no significant effect was observed at 10 mg/kg. These results suggest that β-lactams, 2,5-pyrrolidinediones, azaspirodecatrienediones (ASDT) and dihydropyrroloquinoxalinetriones (DPQT) could be useful for the development of anti-obesity candidate drugs.

Keywords

Anti-obesity agents; GPCR; H3R; Histamine-3 receptor; Post-Ugi modifications; Ugi condensation.

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