Steric trigger as a mechanism for CB1 cannabinoid receptor activation

J Chem Inf Comput Sci. 2004 Jul-Aug;44(4):1466-76. doi: 10.1021/ci040040c.


To determine the moiety that behaves as the steric trigger to activate the CB(1) cannabinoid receptor, conformational properties of the nonclassical cannabinoid CP55244, one of the most potent CB(1) receptor agonists, were characterized by conformational analysis, rotational barrier calculations, and molecular dynamics (MD) simulations. It was shown from the present MD simulations that the torsion angles phi1 and phi4 of the C3 side chain showed the most dramatic change when compared with the ground-state receptor-bound conformation, indicating that rotation around these torsion angles is responsible for releasing the ligand strain energy. Multiple stages would be involved in the ligand conformational change. As a molecular mechanism for the ligand-induced CB(1) receptor conformational change, we propose that the C3 side chain serves as the steric trigger, while the ACD-ring moiety of CP55244 serves as the plug. Steric clash with helices within the binding pocket would induce microconformational adaptation within the protein. This mechanism would suggest that rotational flexibility in a ligand may be as important a determinant of agonist activity as the pharmacophoric elements that can be identified.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Binding Sites
  • Computer Simulation
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Naphthalenes / chemistry
  • Naphthalenes / metabolism
  • Naphthalenes / pharmacology
  • Protein Conformation
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / chemistry*
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Thermodynamics


  • Ligands
  • Naphthalenes
  • Receptor, Cannabinoid, CB1
  • CP 55244