Bivalent ligands as specific pharmacological tools for G protein-coupled receptor dimers - PubMed

Review

Bivalent ligands as specific pharmacological tools for G protein-coupled receptor dimers

Isabelle Berque-Bestel et al. Curr Drug Discov Technol. 2008 Dec.

Abstract

G protein-coupled receptors (GPCRs) are major drug targets and are organized in dimeric/oligomeric complexes. These dimers may be composed of identical (homodimer) or different (heterodimer) receptors. GPCR dimerization provides new opportunities for drug design. Different strategies have been developed to specifically target GPCR dimers. Bivalent ligands, which are composed of two functional pharmacophores linked by a spacer, are among the most promising strategies. Due to the constitutive nature of GPCR dimers, bivalent ligands are expected in most cases to bind to and stabilize preexisting dimers rather then to promote ligand-induced dimerization. Most studies on GPCR dimerization were conducted so far in heterologous expression systems. Due the development of heterodimer-specific tools such as bivalent ligands, dimerization has now been confirmed for an increasing number of receptors in native tissues. In this review, we will discuss general considerations for the design and synthesis of bivalent ligands and present the functional in vitro and in vivo properties of reported bivalent ligands.

Similar articles

• Design of bivalent ligands targeting putative GPCR dimers.

  Huang B, St Onge CM, Ma H, Zhang Y. Huang B, et al. Drug Discov Today. 2021 Jan;26(1):189-199. doi: 10.1016/j.drudis.2020.10.006. Epub 2020 Oct 16. Drug Discov Today. 2021. PMID: 33075471 Free PMC article. Review.

• Dopamine D2 Receptors Dimers: How can we Pharmacologically Target Them?

  Carli M, Kolachalam S, Aringhieri S, Rossi M, Giovannini L, Maggio R, Scarselli M. Carli M, et al. Curr Neuropharmacol. 2018 Jan 30;16(2):222-230. doi: 10.2174/1570159X15666170518151127. Curr Neuropharmacol. 2018. PMID: 28521704 Free PMC article. Review.

• Study of G protein-coupled receptors dimerization: From bivalent ligands to drug-like small molecules.

  Qian M, Sun Z, Chen X, Van Calenbergh S. Qian M, et al. Bioorg Chem. 2023 Nov;140:106809. doi: 10.1016/j.bioorg.2023.106809. Epub 2023 Aug 26. Bioorg Chem. 2023. PMID: 37651896 Review.

• Physiological relevance of GPCR oligomerization and its impact on drug discovery.

  Panetta R, Greenwood MT. Panetta R, et al. Drug Discov Today. 2008 Dec;13(23-24):1059-66. doi: 10.1016/j.drudis.2008.09.002. Epub 2008 Oct 14. Drug Discov Today. 2008. PMID: 18824244 Review.

• Developing a Biased Unmatched Bivalent Ligand (BUmBL) Design Strategy to Target the GPCR Homodimer Allosteric Signaling (cAMP over β-Arrestin 2 Recruitment) Within the Melanocortin Receptors.

  Lensing CJ, Freeman KT, Schnell SM, Speth RC, Zarth AT, Haskell-Luevano C. Lensing CJ, et al. J Med Chem. 2019 Jan 10;62(1):144-158. doi: 10.1021/acs.jmedchem.8b00238. Epub 2018 May 9. J Med Chem. 2019. PMID: 29669202 Free PMC article.

Cited by

• PNA-Based Multivalent Scaffolds Activate the Dopamine D2 Receptor.

  Dix AV, Conroy JL, George Rosenker KM, Sibley DR, Appella DH. Dix AV, et al. ACS Med Chem Lett. 2015 Mar 13;6(4):425-9. doi: 10.1021/ml500478m. eCollection 2015 Apr 9. ACS Med Chem Lett. 2015. PMID: 25893044 Free PMC article.

• The crosstalk between 5-HT_2AR and mGluR2 in schizophrenia.

  Saha S, González-Maeso J. Saha S, et al. Neuropharmacology. 2023 Jun 1;230:109489. doi: 10.1016/j.neuropharm.2023.109489. Epub 2023 Mar 6. Neuropharmacology. 2023. PMID: 36889432 Free PMC article. Review.

• Increasingly accurate dynamic molecular models of G-protein coupled receptor oligomers: Panacea or Pandora's box for novel drug discovery?

  Filizola M. Filizola M. Life Sci. 2010 Apr 10;86(15-16):590-7. doi: 10.1016/j.lfs.2009.05.004. Epub 2009 May 22. Life Sci. 2010. PMID: 19465029 Free PMC article. Review.

• Designing Hybrids Targeting the Cholinergic System by Modulating the Muscarinic and Nicotinic Receptors: A Concept to Treat Alzheimer's Disease.

  Volpato D, Holzgrabe U. Volpato D, et al. Molecules. 2018 Dec 7;23(12):3230. doi: 10.3390/molecules23123230. Molecules. 2018. PMID: 30544533 Free PMC article. Review.

• Adrenergic Agonists Bind to Adrenergic-Receptor-Like Regions of the Mu Opioid Receptor, Enhancing Morphine and Methionine-Enkephalin Binding: A New Approach to "Biased Opioids"?

  Root-Bernstein R, Turke M, Subhramanyam UKT, Churchill B, Labahn J. Root-Bernstein R, et al. Int J Mol Sci. 2018 Jan 17;19(1):272. doi: 10.3390/ijms19010272. Int J Mol Sci. 2018. PMID: 29342106 Free PMC article.

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Bentham Science Publishers Ltd.
  • Ingenta plc