No abstract

The strong inhibition of Human Cytomegalovirus (HCMV) replication by benzimidazole nucleosides, like Triciribine and Maribavir, has prompted us to expand the structure–activity relationships of the benzimidazole series, using as a central core the imidazo[4,5-b]pyridine scaffold. We have thus synthesized a number of novel amino substituted imidazopyridine nucleoside derivatives, which can be considered as 4-(or 7)-aza-d-isosters of Maribavir and have evaluated their potential antiviral activity. The target compounds were synthesized upon glycosylation of suitably substituted 2-aminoimidazopyridines, which were prepared in six steps starting from 2-amino-6-chloropyridine. Even if the new compounds possessed only a slight structural modification when compared to the original drug, they were not endowed with interesting antiviral activity. Even so, three derivatives showed promising cytotoxic potential.

Endocannabinoids (eCBs) are endogenous lipid molecules that activate the cannabinoid receptor 1 (CB1), a G protein coupled receptor (GPCR) that signals primarily through the Gi/o family of G proteins to regulate neurotransmitter release. Consequently, CB1 is an important therapeutic target for several neurological disorders. How eCBs interact with CB1 is not known and the downstream signaling they activate is not well understood. In this study we show that eCBs do not activate Gi1 as much as synthetic cannabinoids. To characterize activation of CB1 by eCB, we formed an eCB analogue-bound (AMG315) CB1-Gi signaling complex for structural studies. The structure reveals differences in the orthosteric ligand binding pocket not seen in the previous CB1 structures, providing insights into the structural determinants of ligand efficacy. In combination with signaling and simulation data, this study provides mechanistic insights into CB1 activation by different classes of ligands, and sheds light on the G protein preferences between endogenous and exogenous ligands.