Terms used to describe receptor allosterism and allosteric ligand actions (see also Note 1)
| Term | Suggested Use |
|---|---|
| Orthosteric site | The binding site/s on a receptor macromolecule that is/are recognized by the endogenous agonist/s for that receptor. |
| Allosteric site | A binding site on a receptor macromolecule that is nonoverlapping and spatially distinct from, but conformationally linked to, the orthosteric binding site. |
| Orthosteric agonist | A ligand that binds to the orthosteric site of a receptor and alters the receptor state, resulting in a biologic response. Conventional orthosteric agonists increase receptor activity, whereas orthosteric inverse agonists reduce it (see also Notes 2 and 3). |
| Allosteric agonist | A ligand that binds to an allosteric site on a receptor macromolecule and alters the receptor state, resulting in a biologic response. Conventional allosteric agonists increase receptor activity, whereas allosteric inverse agonists reduce it (see also Notes 4 and 5). |
| Allosteric modulator | A ligand that modifies the action of an orthosteric agonist, endogenous activator, or antagonist by combining with an allosteric site on the receptor macromolecule. A positive allosteric modulator (PAM) increases the action (affinity and/or efficacy) of an orthosteric agonist, activator, or antagonist, whereas a negative allosteric modulator (NAM) decreases the action (affinity and/or efficacy) of an orthosteric agonist, activator, or antagonist. Note that the term “modulator” is preferred to the terms “effector” or “regulator.” |
| Neutral allosteric ligand | A ligand that combines with an allosteric site on a receptor macromolecule but does not alter the action of a (given) orthosteric agonist, activator, or antagonist. The neutral allosteric ligand (NAL) can, however, prevent the binding of other allosteric ligands to the same allosteric site via a steric interaction and may be a positive or negative allosteric modulator of other orthosteric ligands, activators, or antagonists or allosteric ligands that bind to a different (second) allosteric site on the receptor macromolecule (see also Note 6). Neutral allosteric ligands have also been referred to as “silent allosteric modulators” (SAMs). Note, however, that the terms “neutral” and “ligand” are preferred to the terms “silent” and “modulator” for ligands with neutral cooperativity. This ensures conformity with prior terms, such as “neutral antagonist” and also reflects the fact that if a ligand is neutral, it is not "modulating." |
| Bitopic ligand | A hybrid molecule that concomitantly engages an orthosteric and an allosteric site on a receptor macromolecule via two pharmacologically active pharmacophores (one constituting an orthosteric ligand and the other an allosteric ligand; see also Note 7). |
| Allosteric interaction | An indirect interaction between ligands that bind to spatially distinct, nonoverlapping recognition sites on the receptor macromolecule mediated by a conformational change. |
| Allosteric transition | The isomerization of a receptor macromolecule between different conformational states. |
| Competitive interaction | An interaction between ligands that bind to the same recognition site or to recognition sites that overlap on the receptor macromolecule. A competitive interaction can occur between different orthosteric ligands or between different allosteric ligands provided that each class shares a similar recognition domain on the receptor macromolecule (see also Note 3). |
| Homotropic interaction | An allosteric interaction between structurally identical ligands. |
| Heterotropic interaction | An allosteric interaction between structurally different ligands. |