Dualsteric ligands represent a novel mode of targeting G protein-coupled receptors (GPCRs). These compounds attach simultaneously to both, the orthosteric transmitter binding site and an additional allosteric binding area of a receptor protein. This approach allows the exploitation of favourable characteristics of the orthosteric and the allosteric site by a single ligand molecule. The orthosteric interaction provides high affinity binding and activation of receptors. The allosteric interaction yields receptor subtype-selectivity and, in addition, may modulate both, efficacy and intracellular signalling pathway activation. Insight into the spatial arrangement of the orthosteric and the allosteric site is far advanced in the muscarinic acetylcholine receptor, and the design of dualsteric muscarinic agonists has now been accomplished. Using the muscarinic receptor as a paradigm, this review summarizes the way from suggestive evidence for an orthosteric/allosteric overlap binding to the rational design and experimental validation of dualsteric ligands. As allosteric interactions are increasingly described for GPCRs and as insight into the spatial geometry of ligand/GPCRcomplexes is growing impressively, the rational design of dualsteric drugs is a promising new approach to achieve fine-tuned GPCR-modulation. British Journal of Pharmacology (2010) 159, 997–1008

Rational design of dualsteric GPCR ligands: quests and promise / Mohr, K.; Tränkle, C.; Kostenis, E.; Barocelli, Elisabetta; De Amici, M.; Holzgrabe, U.. - In: BRITISH JOURNAL OF PHARMACOLOGY. - ISSN 0007-1188. - 159(5):(2010), pp. 997-1008. [10.1111/j.1476-5381.2009.00601.x]

Rational design of dualsteric GPCR ligands: quests and promise

BAROCELLI, Elisabetta;
2010-01-01

Abstract

Dualsteric ligands represent a novel mode of targeting G protein-coupled receptors (GPCRs). These compounds attach simultaneously to both, the orthosteric transmitter binding site and an additional allosteric binding area of a receptor protein. This approach allows the exploitation of favourable characteristics of the orthosteric and the allosteric site by a single ligand molecule. The orthosteric interaction provides high affinity binding and activation of receptors. The allosteric interaction yields receptor subtype-selectivity and, in addition, may modulate both, efficacy and intracellular signalling pathway activation. Insight into the spatial arrangement of the orthosteric and the allosteric site is far advanced in the muscarinic acetylcholine receptor, and the design of dualsteric muscarinic agonists has now been accomplished. Using the muscarinic receptor as a paradigm, this review summarizes the way from suggestive evidence for an orthosteric/allosteric overlap binding to the rational design and experimental validation of dualsteric ligands. As allosteric interactions are increasingly described for GPCRs and as insight into the spatial geometry of ligand/GPCRcomplexes is growing impressively, the rational design of dualsteric drugs is a promising new approach to achieve fine-tuned GPCR-modulation. British Journal of Pharmacology (2010) 159, 997–1008
2010
Rational design of dualsteric GPCR ligands: quests and promise / Mohr, K.; Tränkle, C.; Kostenis, E.; Barocelli, Elisabetta; De Amici, M.; Holzgrabe, U.. - In: BRITISH JOURNAL OF PHARMACOLOGY. - ISSN 0007-1188. - 159(5):(2010), pp. 997-1008. [10.1111/j.1476-5381.2009.00601.x]
File in questo prodotto:
File Dimensione Formato  
BrJPharmacol2010EB.pdf

non disponibili

Tipologia: Documento in Post-print
Licenza: Creative commons
Dimensione 520.11 kB
Formato Adobe PDF
520.11 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
AbstBrJPharmacol2010.pdf

non disponibili

Tipologia: Abstract
Licenza: Creative commons
Dimensione 52.01 kB
Formato Adobe PDF
52.01 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

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/11381/2308310
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 105
  • ???jsp.display-item.citation.isi??? 99
social impact