ci9b00577_si_001.pdf (2.48 MB)
Prediction and Experimental Confirmation of Novel Peripheral Cannabinoid‑1 Receptor Antagonists
journal contribution
posted on 2019-09-04, 19:35 authored by Shayma El-Atawneh, Shira Hirsch, Rivka Hadar, Joseph Tam, Amiram GoldblumSmall 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.