'Allosteric' GPCR agonists and antagonists

'Allosteric' GPCR agonists and antagonists

While most drugs that act as agonists or agonists of GPCR appear to bind competitively, i.e. to the binding site of the physiological agonist, several compounds have been report-ed to bind to other sites, allowing them to bind simultaneously with the physiological agonist. Binding of such `al-losteric' effectors may promote or reduce activation by the physiological agonist without actually causing any effect in the absence of the latter. As an example, the interaction of two molecules with A<sub>1</sub> adenosine receptors<sup>5</sup> is shown in Figure 8.5. While the `allosteric' molecule in question (PD 81,723) does indeed enhance binding of the agonist (cyclohexyladenosine) at intermediate concentrations, it actually inhibits it at higher concentrations, which is not at all in keeping with the expectations for a true allosteric effector. An alternative interpretation is that the A1 adenosine receptor is oligomeric, and that cyclohexyladenosine and PD 81,723 bind to the regular binding site but on separate subunits. If binding is to separate subunits were cooperative, one would expect a pattern like the one observed here.