When simple agonism is not enough: emerging modalities of GPCR ligands

Nicola J. Smith (1) , Kirstie A. Bennett (1) , Graeme Milligan (1)

1 College of Medical, Veterinary and Life Sciences [Glasgow]

Recent advances in G protein-coupled receptors have challenged traditional definitions of agonism, antagonism, affinity and efficacy. The discovery of agonist functional selectivity and receptor allosterism has meant researchers have an expanded canvas for designing and discovering novel drugs. Here we describe modes of agonism emerging from the discovery of functional selectivity and allosterism. We discuss the concept of ago-allosterism, where ligands can initiate signaling by themselves and influence the actions of another ligand at the same receptor. We introduce the concept of dualsteric ligands that consist of distinct elements which bind to each of the orthosteric and an allosteric domain on a single receptor to enhance subtype selectivity. Finally, the concept that efficacy should be defined by the activity of an endogenous ligand will be challenged by the discovery that some ligands act as 'super-agonists' in specific pathways or at certain receptor mutations.

Mots clés: G protein-coupled receptor; Functional selectivity; Allosterism; Ago-allosterism; Dualsteric ligand; Super-agonism

Nicola J. Smith, Kirstie A. Bennett, Graeme Milligan. When simple agonism is not enough: emerging modalities of GPCR ligands. Molecular and Cellular Endocrinology, 2010, 331 (2), pp.241. ⟨10.1016/j.mce.2010.07.009⟩. ⟨hal-00654484⟩