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Dualsteric Ligands

Dualsteric (or bitopic) ligands represent a novel mode of targeting G protein-coupled receptors (GPCRs). These compounds attach simultaneously to the orthosteric binding site and an additional allosteric binding area of the receptor protein.

This approach allows the exploitation of favourable characteristics of the orthosteric and the allosteric site by a single molecule. The orthosteric interaction enables high affinity binding and activation of the receptor. The allosteric interaction can provide with receptor subtype-selectivity and, in addition, may modulate efficacy and intracellular signalling pathway activation.

We design and synthesize dualsteric ligands of acetylcholine muscarinic receptors (mAChRs) via molecular hybridization of orthosteric agonists and allosteric modulators. In addition to a potential therapeutic use thanks to their ability to fine-tune the cellular responses mediated by mAChRs, these molecules can be used as valuable research tools for a label-free approach to gain deeper insight into the geometry of activation-related conformational changes of GPCRs.

Selected Publications

Guerriero C, Matera C, Del Bufalo D, De Amici M, Conti L, Dallanoce C, Tata AM. The Combined Treatment with Chemotherapeutic Agents and the Dualsteric Muscarinic Agonist Iper-8-Naphthalimide Affects Drug Resistance in Glioblastoma Stem Cells. Cells. 2021 Jul 24;10(8):1877. doi: 10.3390/cells10081877. PMID: 34440646; PMCID: PMC8391681.

Holze J, Bermudez M, Pfeil EM, Kauk M, Bödefeld T, Irmen M, Matera C, Dallanoce C, De Amici M, Holzgrabe U, König GM, Tränkle C, Wolber G, Schrage R, Mohr K, Hoffmann C, Kostenis E, Bock A. Ligand-Specific Allosteric Coupling Controls G-Protein-Coupled Receptor Signaling. ACS Pharmacol Transl Sci. 2020 Sep 2;3(5):859-867. doi: 10.1021/acsptsci.0c00069. PMID: 33073186; PMCID: PMC7551708.

Matera C, Flammini L, Riefolo F, Domenichini G, De Amici M, Barocelli E, Dallanoce C, Bertoni S. Novel analgesic agents obtained by molecular hybridization of orthosteric and allosteric ligands. Eur J Pharmacol. 2020 Jun 5;876:173061. doi: 10.1016/j.ejphar.2020.173061. Epub 2020 Mar 13. PMID: 32179086.

Maspero M, Volpato D, Cirillo D, Yuan Chen N, Messerer R, Sotriffer C, De Amici M, Holzgrabe U, Dallanoce C. Tacrine-xanomeline and tacrine-iperoxo hybrid ligands: Synthesis and biological evaluation at acetylcholinesterase and M₁ muscarinic acetylcholine receptors. Bioorg Chem. 2020 Mar;96:103633. doi: 10.1016/j.bioorg.2020.103633. Epub 2020 Jan 30. PMID: 32032848.

Cristofaro I, Spinello Z, Matera C, Fiore M, Conti L, De Amici M, Dallanoce C, Tata AM. Activation of M2 muscarinic acetylcholine receptors by a hybrid agonist enhances cytotoxic effects in GB7 glioblastoma cancer stem cells. Neurochem Int. 2018 Sep;118:52-60. doi: 10.1016/j.neuint.2018.04.010. Epub 2018 Apr 24. PMID: 29702145.

Bock A, Bermudez M, Krebs F, Matera C, Chirinda B, Sydow D, Dallanoce C, Holzgrabe U, De Amici M, Lohse MJ, Wolber G, Mohr K. Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor. J Biol Chem. 2016 Jul 29;291(31):16375-89. doi: 10.1074/jbc.M116.735431. Epub 2016 Jun 13. PMID: 27298318; PMCID: PMC4965584.

Matera C, Flammini L, Quadri M, Vivo V, Ballabeni V, Holzgrabe U, Mohr K, De Amici M, Barocelli E, Bertoni S, Dallanoce C. Bis(ammonio)alkane-type agonists of muscarinic acetylcholine receptors: synthesis, in vitro functional characterization, and in vivo evaluation of their analgesic activity. Eur J Med Chem. 2014 Mar 21;75:222-32. doi: 10.1016/j.ejmech.2014.01.032. Epub 2014 Jan 25. PMID: 24534538.

Bock A, Merten N, Schrage R, Dallanoce C, Bätz J, Klöckner J, Schmitz J, Matera C, Simon K, Kebig A, Peters L, Müller A, Schrobang-Ley J, Tränkle C, Hoffmann C, De Amici M, Holzgrabe U, Kostenis E, Mohr K. The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling. Nat Commun. 2012;3:1044. doi: 10.1038/ncomms2028. PMID: 22948826; PMCID: PMC3658004.