Prediction and Experimental Confirmation of Novel Peripheral Cannabinoid-1 Receptor Antagonists

Shayma El-Atawneh, Shira Hirsch, Rivka Hadar, Joseph Tam*, Amiram Goldblum

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Small molecules targeting peripheral CB1 receptors have therapeutic potential in a variety of disorders including obesity-related, hormonal, and metabolic abnormalities, while avoiding the psychoactive effects in the central nervous system. We applied our in-house algorithm, iterative stochastic elimination, to produce a ligand-based model that distinguishes between CB1R antagonists and random molecules by physicochemical properties only. We screened ∼2 million commercially available molecules and found that about 500 of them are potential candidates to antagonize the CB1R. We applied a few criteria for peripheral activity and narrowed that set down to 30 molecules, out of which 15 could be purchased. Ten out of those 15 showed good affinity to the CB1R and two of them with nanomolar affinities (Ki of ∼400 nM). The eight molecules with top affinities were tested for activity: two compounds were pure antagonists, and five others were inverse agonists. These molecules are now being examined in vivo for their peripheral versus central distribution and subsequently will be tested for their effects on obesity in small animals.

Original languageAmerican English
Pages (from-to)3996-4006
Number of pages11
JournalJournal of Chemical Information and Modeling
Volume59
Issue number9
DOIs
StatePublished - 23 Sep 2019

Bibliographical note

Publisher Copyright:
© 2019 American Chemical Society.

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