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Structural basis of selective cannabinoid CB2 receptor activation.

<div class='caption-title'>Chemical structures.</div>
<div class='caption-title'>Cryo-EM structures of CB2R-Gi complexes.</div>
<div class='caption-title'>Key interactions between CB2R and agonists.</div>
Li X, Chang H, Bouma J, de Paus LV, Mukhopadhyay P, Paloczi J, Mustafa M, van der Horst C, Kumar SS, Wu L, Yu Y, van den Berg RJBHN, Janssen APA, Lichtman A, Liu ZJ, Pacher P, van der Stelt M, Heitman LH, Hua T
OpenAccess logo Nat Commun 14 1447 (2023)
Related entries: 8guq, 8gur, 8gut

Cited: 6 times
EuropePMC logo PMID: 36922494

Abstract

Cannabinoid CB2 receptor (CB2R) agonists are investigated as therapeutic agents in the clinic. However, their molecular mode-of-action is not fully understood. Here, we report the discovery of LEI-102, a CB2R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate the selective CB2R activation by binding kinetics, site-directed mutagenesis, and cryo-EM studies. We identify key residues for CB2R activation. Highly lipophilic HU308 and the endocannabinoids, but not the more polar LEI-102, APD371, and CP55,940, reach the binding pocket through a membrane channel in TM1-TM7. Favorable physico-chemical properties of LEI-102 enable oral efficacy in a chemotherapy-induced nephropathy model. This study delineates the molecular mechanism of CB2R activation by selective agonists and highlights the role of lipophilicity in CB2R engagement. This may have implications for GPCR drug design and sheds light on their activation by endogenous ligands.

Reviews citing this publication (5)

  1. Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years. Maccarrone M, Di Marzo V, Gertsch J, Grether U, Howlett AC, Hua T, Makriyannis A, Piomelli D, Ueda N, van der Stelt M. Pharmacol Rev 75 885-958 (2023)
  2. Molecular mechanisms of pain in acute pancreatitis: recent basic research advances and therapeutic implications. Wu Y, Han C, Luo R, Cai W, Xia Q, Jiang R, Ferdek PE, Liu T, Huang W. Front Mol Neurosci 16 1331438 (2023)
  3. Rational Design, Synthesis, and Evaluation of Fluorescent CB2 Receptor Ligands for Live-Cell Imaging: A Comprehensive Review. Bhattacharjee P, Iyer MR. Pharmaceuticals (Basel) 16 1235 (2023)
  4. Structural and functional insights into the G protein-coupled receptors: CB1 and CB2. Brust CA, Swanson MA, Bohn LM. Biochem Soc Trans 51 1533-1543 (2023)
  5. Synthetic Pathways to Non-Psychotropic Phytocannabinoids as Promising Molecules to Develop Novel Antibiotics: A Review. Alfei S, Schito GC, Schito AM. Pharmaceutics 15 1889 (2023)

Articles citing this publication (1)

  1. The Leu/Val6.51 Side Chain of Cannabinoid Receptors Regulates the Binding Mode of the Alkyl Chain of Δ9-Tetrahydrocannabinol. Llinas Del Torrent C, Raïch I, Gonzalez A, Casajuana-Martin N, Lillo J, Rebassa JB, Ferreiro-Vera C, Sánchez de Medina V, Franco R, Navarro G, Pardo L. J Chem Inf Model 63 5927-5935 (2023)


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