BMS 794833 1174046-72-0 decreased cAMP formation by 80% in hCB2 expressing cells

212 2. The reason for the more modest 40 50% decrease seen in both rodent CB2 cell lines is not clear, but may be due to differences BMS BMS 794833 1174046-72-0 794833 1174046-72-0 in coupling of the receptor to the G protein complex. An increase in cAMP levels above those stimulated by forskolin was observed in response to the CB2 antagonist SR144528, as would be expected based on this compound,s characterization as an inverse agonist. Inverse agonism is an operative term used to describe inhibition of basal coupling or constitutive activity of the ligand unbound receptor.
As shown by its higher maximal response to either SR144528 or R AM1241, the buy BMS 794833 cells with the mCB2 receptors would appear to have a higher level of constitutive activity than those with the human or rat receptors, perhaps corresponding to a more effective coupling of this receptor to the cellular signal transduction machinery.
R,S AM1241 inhibited cAMP production stimulated by treatment of buy BMS 794833 the h CB2 expressing cell line with 1 mM forskolin, consistent with this racemate acting as an agonist of hCB2 receptors. The forskolin concentration used in our studies was lower than those used in a similar study, wherein it was reported that the function of R,S AM1241 in cyclase assays was sensitive to the concentration of forskolin used to stimulate hCB2 expressing cells.
In our characterization of the rodent receptors, R,S AM1241 demonstrated inverse agonist properties at the same concentration of forskolin that was associated with agonist activity at the hCB2 receptors.
S AM1241 was seen to be an agonist at human, mouse and rat CB2 receptors, whereas R AM1241 was observed to be an agonist at the human receptor and an inverse agonist in the cells with the rodent receptors. The functional properties of the racemate are dominated by those of the R enantiomer, reflecting its more than 40 fold higher CB2 affinity compared with the S enantiomer. In an analysis of racemic AM1241 in hCB2 receptor assays, functional activity varied depending on the end point that was measured. The authors proposed the diverse functional effects of R,S AM1241 as a case of protean agonism, a phenomenon wherein the state of constitutive receptor activity can determine the functional effect of a ligandreceptor interaction.
Under the protean agonist hypothesis, two receptor states, a ligand bound and a constitutively active, ligand unbound form, compete for G proteins.
If the efficacy of the constitutively active receptor is higher than that of the ligand bound receptor, then the protean agonist, by inducing a less active receptor conformation, will appear as an inverse agonist. In the absence of constitutive activity, the same ligand will act as a partial agonist. Differing levels of receptor activation in different cell based assay systems can thus suffice to produce varying functional outcomes. It is tempting, therefore, to speculate that the inverse agonist activity of R AM1241 at the rodent CB2 receptors, in contrast to its agonist activity at the human receptor, results from different levels of CB2 constitutive activity between our rodent and human receptor expression systems, giving rise to a case of protean agonism. However, the observation that the human receptor displays higher basal activity t