RT Journal Article
SR Electronic
T1 CB1 Receptor Allosteric Modulators Display both Agonist and Signaling Pathway Specificity
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.112.080879
DO 10.1124/mol.112.080879
A1 Gemma L Baillie
A1 James Horswill
A1 Sharon Anavi-Goffer
A1 Patricia H. Reggio
A1 Mary E. Abood
A1 Daniele Bolognini
A1 Sean McAllister
A1 Philip G Strange
A1 Gary J. Stephens
A1 Roger G Pertwee
A1 Ruth A Ross
YR 2012
UL http://molpharm.aspetjournals.org/content/early/2012/11/15/mol.112.080879.abstract
AB We have previously identified allosteric modulators of the cannabinoid CB1 receptor (Org 27569, PSNCBAM-1) which display a contradictory pharmacological profile: increasing the specific binding of the CB1 receptor agonist [3H]CP55940 but producing a decrease in CB1 receptor agonist efficacy. Here we investigated the effect one or both compounds in a broad range of signalling endpoints linked to CB1 receptor activation. We assessed the effect of these compounds on CB1, receptor agonist-induced [35S]GTPγS binding, inhibition and stimulation of forskolin-stimulated cAMP production, phosphorylation of ERK, and β arrestin recruitment. We also investigated the effect of these allosteric modulators on CB1 agonist binding kinetics. Both compounds display ligand dependence, being significantly more potent as modulators of CP55940 signalling as compared to WIN55212 and having little effect on [3H]WIN55212 binding. Org 27569 displays biased antagonism whereby it inhibits: agonist-induced [35S]GTPγS binding, simulation (Gαs mediated) and inhibition (Gαs mediated) of cAMP production and β arrestin recruitment. In contrast, it acts as an enhancer of agonist-induced ERK phosphoryation. Alone, the compound can act also as an allosteric agonist, increasing cAMP production and ERK phosphorylation. We find that in both saturation and kinetic binding experiments, the Org 27569 and PSNCBAM-1 appeared to influence only orthosteric ligand maximum occupancy rather than affinity. The data indicate that the allosteric modulators share a common mechanism whereby they increase available high affinity CB1 agonist binding sites. The receptor conformation stabilised by the allosterics appears to induce signalling and also selectively traffics orthosteric agonist signalling via the ERK phosphorylation pathway.