**6.2 Partial GPCR activation: Agonist efficacy**

Some compounds seem less efficient than others to activate G protein coupled receptors: the rate of G protein activation by agonist-bound receptors varies depending on the ligand. Two explanations are usually put forward to account for this very common observation: partial agonists might stabilize the same "active" receptor conformation as full agonists but to a lesser extent; alternatively, they might stabilize an alternative receptor conformation, not quite as appropriate as the conformation induced by full agonists for G protein activation. These two explanations are non-exclusive and both explanations might in fact be correct at least where β2-adrenergic agonists are concerned (Bhattacharya and Vaidehi, 2010). Indeed, while dopamine was predicted to stabilize (less efficiently) the same "opened" receptor conformation as norepinephrine, salbutamol was predicted to stabilize a slightly different, less opened, receptor conformation. Yet a third explanation has been suggested for muscarinic receptors: agonists dissociate from muscarinic receptors with a rate constant comparable to the G protein exchange reaction rate. The efficacy of agonists activating M3 muscarinic receptors was correlated with their dissociation rate constant, suggesting that the G protein activation reaction can be aborted prematurely if the agonist dissociates too early in the reaction cycle (Sykes *et al.*, 2009).
