Allosteric receptor ligands bind to a recognition site that is distinct from the binding site of the endogenous messenger molecule. As a consequence, allosteric agents may attach to receptors that are already transmitter-bound. Ternary complex formation opens an avenue to qualitatively new drug actions at G protein-coupled receptors (GPCRs), in particular receptor subtype selective potentiation of endogenous transmitter action. Consequently, suitable exploitation of allosteric recognition sites as alternative molecular targets could pave the way to a drug discovery paradigm different from those aimed at mimicking or blocking the effects of endogenous (orthosteric) receptor activators. The number of allosteric ligands reported to modulate GPCR function is steadily increasing and some have already reached routine clinical use. This review aims at introducing into this fascinating field of drug discovery and at providing an overview about the achievements that have already been made. Various case examples will be discussed in the framework of GPCR classification (Class A, B, and C receptors). In addition, the behavior of hybrid derivatives incorporating both an allosteric and an orthosteric fragment in a common molecular skeleton will be illustrated.

Allosteric ligands for G protein-coupled receptors : a novel strategy with attractive therapeutic opportunities / M. De Amici, C.M.L. Dallanoce, U. Holzgrabe, C. Tränkle, K. Mohr. - In: MEDICINAL RESEARCH REVIEWS. - ISSN 0198-6325. - 30:3(2010), pp. 463-549. [10.1002/med.20166]

Allosteric ligands for G protein-coupled receptors : a novel strategy with attractive therapeutic opportunities

M. De Amici
Primo
;
C.M.L. Dallanoce
Secondo
;
2010

Abstract

Allosteric receptor ligands bind to a recognition site that is distinct from the binding site of the endogenous messenger molecule. As a consequence, allosteric agents may attach to receptors that are already transmitter-bound. Ternary complex formation opens an avenue to qualitatively new drug actions at G protein-coupled receptors (GPCRs), in particular receptor subtype selective potentiation of endogenous transmitter action. Consequently, suitable exploitation of allosteric recognition sites as alternative molecular targets could pave the way to a drug discovery paradigm different from those aimed at mimicking or blocking the effects of endogenous (orthosteric) receptor activators. The number of allosteric ligands reported to modulate GPCR function is steadily increasing and some have already reached routine clinical use. This review aims at introducing into this fascinating field of drug discovery and at providing an overview about the achievements that have already been made. Various case examples will be discussed in the framework of GPCR classification (Class A, B, and C receptors). In addition, the behavior of hybrid derivatives incorporating both an allosteric and an orthosteric fragment in a common molecular skeleton will be illustrated.
Activation cooperativity; Allosteric agonist; Allosteric antagonist; Allosteric inverse agonist; B; Binding cooperativity; C GPCRs; Dualsteric ligands; Family A; Ternary complex
Settore CHIM/08 - Chimica Farmaceutica
Settore BIO/14 - Farmacologia
2010
Article (author)
File in questo prodotto:
Non ci sono file associati a questo prodotto.
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/145743
Citazioni
  • ???jsp.display-item.citation.pmc??? 27
  • Scopus 78
  • ???jsp.display-item.citation.isi??? 73
social impact