GAT-211

Cannabis sativa is known for its therapeutic benefit in various diseases including pain relief by targeting cannabinoid receptors. The primary component of cannabis, Δ9-tetrahydrocannabinol (THC), and other agonists engage the orthosteric site of CB1, activating both Gi and β-arrestin signaling pathways. The activation of diverse pathways could result in on-target side effects and cannabis addiction, which may hinder therapeutic potential. A significant challenge in pharmacology is the design of a ligand that can modulate specific signaling of CB1. By leveraging insights from the structure–function selectivity relationship (SFSR), we have identified Gi signaling–biased agonist-allosteric modulators (ago-BAMs). Further, two cryoelectron microscopy (cryo-EM) structures reveal the binding mode of ago-BAM at the extrahelical allosteric site of CB1. Combining mutagenesis and pharmacological studies, we elucidated the detailed mechanism of ago-BAM-mediated biased signaling. Notably, ago-BAM CB-05 demonstrated analgesic efficacy with fewer side effects, minimal drug toxicity and no cannabis addiction in mouse pain models. In summary, our finding not only suggests that ago-BAMs of CB1 provide a potential nonopioid strategy for pain management but also sheds light on BAM identification for GPCRs.

Hydrogen bond donating (HBD) heterogeneous organocatalysis has come to light as a powerful surrogate to Lewis acid activation toward manufacturing biol. important C-C bonds.Notwithstanding the emergence of urea as a functionally diverse moiety to drive homogeneous HBD reactions, its catalytic competency is often muted by self-quenching behavior.Keeping this in perspective, spatial isolation of catalytically active urea functionality inside a porous framework can alleviate this pitfall, rendering a potential solutionThe current work reports the fabrication of a porous urea network (IPpop-1) as a superior heterogeneous HBD catalyst toward Friedel-Crafts alkylation of β-nitrostyrene and indole (yield up to 99%) under mild conditions advocating green chem.Exptl. evidence that supports the critical step of the catalytic reaction leading to a plausible mechanism was unveiled along with theor. assistance.Addnl., the versatile bifunctional nature of the catalyst was established from its competence in catalyzing multicomponent Knoevenagel-Michael condensation and cyanosilylation reactions efficiently.One-pot cascade catalysis was also achieved under milder reaction conditions with excellent product yields exploiting the dual active sites of IPpop-1.Pertaining to practicality, spherical composite beads were fabricated to perform continuous flow multicomponent Knoevenagel-Michael condensation without compromising the catalytic activity of IPpop-1.Furthermore, regeneration of the spent catalyst (up to 10 cycles) and scalability combined with wide substrate tolerance manifested conceptual feasibility of the polymer catalyst.