Fourteen novel alkylindole compounds were synthesized that activate unidentified G protein-coupled receptors distinct from CB1 and CB2, with potency in the low nanomolar range.
Cannabinoid receptor pharmacologists, medicinal chemists, and GPCR researchers.
1.1 nM EC50for compound 12 at unidentified AI-sensitive GPCRs, distinct from known cannabinoid receptors
What the researchers found
Compounds 10 and 12 activated AI-sensitive GPCRs with EC50 values of 3.5 and 1.1 nM through pertussis toxin-sensitive Gi/o coupling. Three structural features distinguish AI-GPCR binding from CB1R/CB2R binding.
Why it matters
The existence of uncharacterized cannabinoid-like receptors suggests the endocannabinoid system is more complex than currently understood, with implications for drug development.
The numbers in context
14 novel AI analogues synthesized. Compound 10 EC50=3.5 nM, Compound 12 EC50=1.1 nM. 5 compounds distinguished high/low affinity receptor states. 3 structural features identified by pharmacophore modeling.
How the study worked
Medicinal chemistry synthesis of 14 alkylindole analogues with pharmacological characterization via [35S]GTPyS and radioligand binding in HEK293 cells, plus in silico pharmacophore modeling.
Who was studied
Not applicable (in vitro medicinal chemistry and pharmacology study).
What this study cannot tell us
Molecular identity of AI-sensitive GPCRs remains unknown. HEK293 cell results may not reflect in vivo pharmacology. Selectivity over all other GPCRs not established.
How to read the evidence
Rigorous medicinal chemistry and pharmacology study; fundamental research expanding knowledge of cannabinoid-like signaling.
When this study was published
Recent drug discovery research.
The bigger picture
These novel chemical tools enable investigation of previously uncharacterized cannabinoid-like receptors, potentially revealing new therapeutic targets beyond the established CB1/CB2 system.
Replication
Novel receptor discovery; molecular identification and in vivo characterization needed.
Funding
Not specified in abstract
Conflicts of interest
Not specified in abstract
Questions still open
- What is the molecular identity of these AI-sensitive GPCRs?
- What physiological roles do these unknown receptors play?
Read the original research
Design, synthesis, and evaluation of substituted alkylindoles that activate G protein-coupled receptors distinct from the cannabinoid CB1 and CB2 receptors.
European journal of medicinal chemistry, 249, 115123
Citation
Kline, Toni; Xu, Cong; Kreitzer, Faith R; Hurst, Dow P; Eldeeb, Khalil M; Wager-Miller, Jim; Olivas, Kathleen; Hepburn, Seon A; Huffman, John W; Mackie, Ken; Howlett, Allyn C; Reggio, Patricia; Stella, Nephi. (2023). Design, synthesis, and evaluation of substituted alkylindoles that activate G protein-coupled receptors distinct from the cannabinoid CB1 and CB2 receptors.. European journal of medicinal chemistry, 249, 115123. https://doi.org/10.1016/j.ejmech.2023.115123