Title: Parallel Synthesis of Hexahydrodiimidazodiazepines Heterocyclic Peptidomimetics and Their in Vitro and in Vivo Activities at μ (MOR), δ (DOR), and κ (KOR) Opioid Receptors.

Journal: journal of Medicinal Chemistry

Authors: Shainnel O. Eans, Michelle L. Ganno, Elisa Mizrachi, Richard A. Houghten, Colette T. Dooley, Jay P. McLaughlin, and Adel Nefzi

Year published: 2016

Link: https://pubs.acs.org/doi/pdf/10.1021/jm501637c

This paper investigates the antinociceptive activity of diimidazodiazepine 14. Diimidazodiazepine 14 is a heterocyclic peptide modified from reduced tripeptides. The essence of this modification was to make the peptide a peripheral selective KOR. Peripheral selectivity results in inability to feel pain without the side effects mediated MOR, DOR,KOR. These effects include, respiratory depression, constipation and addiction.

Peripheral selectivity of diimidazodiazepine 14 was calculated after IP testing in a mouse withdrawal assay and oral absorbance together with CNS penetration were confirmed by collecting profused brain from mice. LC results confirmed  minimal blood−brain barrier penetration by the peptide after oral administration