Allosteric modulation of G-protein-coupled receptors

Abstract

Allosteric modulation of G-protein-coupled receptors may provide an alternative approach for selective receptor interactions. The article is an overview of allosteric modulators enhancing or diminishing the effects of (endogenous) agonists or antagonists on a variety of G-protein-coupled receptors such as muscarinic, α-adrenergic, serotoninergic, dopaminergic, adenosine, metabotropic glutamate and Ca²⁺ receptors. Efficacious allosteric modulators have been published for the serotonin receptor (5-HT moduline; oleamide), the dopamine receptor (cyclic analogues of the tripeptide prolyl-leucyl-glycinamide), the metabotropic glutamate receptor (CPCCOET (mglu1); MPEP (mglu5)) and the Ca²⁺ receptor (NPS R-568; NPS 2143). Leads are available for the muscarinic (Ach) receptor (K5720) and the α_2A-adrenoceptor (agmatine). SCH-202676 and amiloride analogues are nonselective allosteric modifiers interacting with several different receptors. They may not be suitable as leads for future drugs but such compounds may be used for screening purposes.

• allosteric modulators
• G-protein-coupled receptors
• negative co-operativity
• positive co-operativity.