Polypharmacology refers to the development and the use of pharmaceutical agents that act on multiple targets or disease pathways. It is generally thought that complex diseases – such as central nervous system diseases and cancer – may require complex therapeutic approaches. In this respect, a drug that hits multiple sensitive nodes belonging to a network of interacting targets offers the potential for higher efficacy and may limit drawbacks generally arising from the use of a single-target drug or a combination of multiple drugs.
Dual-target (or multi-target) ligands are generally designed using a strategy of molecular hybridization, a new concept in drug design and development based on the combination of pharmacophoric moieties of different bioactive substances to produce a new hybrid compound able to modulate multiple targets of interest. Using this strategy, we develop bifunctional ligands that target two different neurotransmitter receptors to tackle complex neurological disorders.
- Matera C, Bono F, Pelucchi S, Collo G, Bontempi L, Gotti C, Zoli M, De Amici M, Missale C, Fiorentini C, Dallanoce C. The novel hybrid agonist HyNDA-1 targets the D3R-nAChR heteromeric complex in dopaminergic neurons. Biochem Pharmacol. 2019 May;163:154-168. doi: 10.1016/j.bcp.2019.02.019. Epub 2019 Feb 14. PMID: 30772268.
- Matera C, Pucci L, Fiorentini C, Fucile S, Missale C, Grazioso G, Clementi F, Zoli M, De Amici M, Gotti C, Dallanoce C. Bifunctional compounds targeting both D2 and non-α7 nACh receptors: design, synthesis and pharmacological characterization. Eur J Med Chem. 2015 Aug 28;101:367-83. doi: 10.1016/j.ejmech.2015.06.039. Epub 2015 Jun 20. PMID: 26164842.