Schematic representation of common phenotypes of GPCR allosteric modulators acting cooperatively with an orthosteric agonist. Diagramed are the potential effects of a positive allosteric modulator (PAM), negative allosteric modulator (NAM), and neutral allosteric ligand (NAL) on the signaling output of an orthosteric agonist. The comparison illustrates that a PAM can potentiate the signaling output of the orthosteric agonist by engaging the GPCR at a site distinct from the orthosteric site and enhancing the potency, affinity, and/or efficacy of the orthosteric agonist at the receptor, whereas a NAM has the opposite effect. In contrast, a NAL occupies the GPCR allosteric ligand-binding site without effect on the information transmission. Not shown are allosteric agonists with intrinsic activity in addition to their allosteric effects, endowing them, for example, with the capability of directly activating the receptor (e.g., ago-PAMs).