On the G-Protein-Coupled Receptor Heteromers and Their Allosteric Receptor-Receptor Interactions in the Central Nervous System: Focus on Their Role in Pain Modulation

Figure 2

Intra- and intermolecular allosteric receptor-receptor interactions. Allosteric mechanisms make possible the integrative activity taking place intramolecularly in monomers (left) or intermolecularly in homo-/heteromers (right). As one example of the intramolecular allosteric mechanisms is the allosteric binding of salvinorin A to the extracellular site of MOR, which partially affects the activity of the orthosteric MOR binding site via a conformational change [105]. Intermolecular allosteric mechanisms take place through the formation of different types of receptor homo-/heteromers and receptor/protein complexes which can change the function of an individual receptor present in a homomer or heteromer. Another example based on the intermolecular heteromer interactions is the use of heterobivalent ligands containing a MOR agonist and an DOR antagonist linked through a spacer of variable size which may function as useful molecular probes for targeting the MOR-DOR heteromer and in this way counteracting the DOR antagonism on MOR function. Such compounds may have a potential use in pharmacotherapy of pain.