Nicotinic Acetylcholine Receptor Ligands
Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that mediate fast neurotransmission in the central and peripheral nervous systems. They are broadly distributed across the peripheral nervous system (PNS) and central nervous system (CNS) where they play a wide range of functions from the mediation of different cognitive processes to synaptic transmission from nerves to muscle.
Homomeric α7 nAChRs and heteromeric α4β2 nAChRs are predominantly expressed in the human brain where they contribute to the pathogenesis of a range of neurological disorders including Alzheimer’s disease, Parkinson’s disease, schizophrenia and depression. α7 and α4β2 nAChRs also contribute to other non-neurological diseases, including a correlation of both subtypes with nicotine addiction and nicotine-induced behaviors and the overexpression of α7 nAChRs associated with small-cell lung carcinomas. Given their potential roles in disease development and progression, α7 and α4β2 nAChRs are currently one of the most studied nAChR subtypes.
In our lab we have a long history of research in this field and we are keen on developing novel ligands (agonists, silent agonists, antagonists, positive allosteric modulators) of nAChRs for therapeutic and investigational purposes.
- Pismataro MC, Horenstein NA, Stokes C, Quadri M, De Amici M, Papke RL, Dallanoce C. Design, synthesis, and electrophysiological evaluation of NS6740 derivatives: Exploration of the structure-activity relationship for alpha7 nicotinic acetylcholine receptor silent activation. Eur J Med Chem. 2020 Nov 1;205:112669. doi: 10.1016/j.ejmech.2020.112669. Epub 2020 Jul 28. PMID: 32810771; PMCID: PMC7590973.
- Matera C, Quadri M, Sciaccaluga M, Pomè DY, Fasoli F, De Amici M, Fucile S, Gotti C, Dallanoce C, Grazioso G. Modification of the anabaseine pyridine nucleus allows achieving binding and functional selectivity for the α3β4 nicotinic acetylcholine receptor subtype. Eur J Med Chem. 2016 Jan 27;108:392-405. doi: 10.1016/j.ejmech.2015.11.045. Epub 2015 Dec 5. PMID: 26706350.
- Di Cesare Mannelli L, Pacini A, Matera C, Zanardelli M, Mello T, De Amici M, Dallanoce C, Ghelardini C. Involvement of α7 nAChR subtype in rat oxaliplatin-induced neuropathy: effects of selective activation. Neuropharmacology. 2014 Apr;79:37-48. doi: 10.1016/j.neuropharm.2013.10.034. Epub 2013 Nov 10. PMID: 24225197.
- Pucci L, Grazioso G, Dallanoce C, Rizzi L, De Micheli C, Clementi F, Bertrand S, Bertrand D, Longhi R, De Amici M, Gotti C. Engineering of α-conotoxin MII-derived peptides with increased selectivity for native α6β2* nicotinic acetylcholine receptors. FASEB J. 2011 Nov;25(11):3775-89. doi: 10.1096/fj.10-179853. Epub 2011 Jul 21. PMID: 21778325.
- Dallanoce C, Magrone P, Matera C, Frigerio F, Grazioso G, De Amici M, Fucile S, Piccari V, Frydenvang K, Pucci L, Gotti C, Clementi F, De Micheli C. Design, synthesis, and pharmacological characterization of novel spirocyclic quinuclidinyl-Δ2-isoxazoline derivatives as potent and selective agonists of α7 nicotinic acetylcholine receptors. ChemMedChem. 2011 May 2;6(5):889-903. doi: 10.1002/cmdc.201000514. Epub 2011 Mar 1. PMID: 21365765.
- Rizzi L, Dallanoce C, Matera C, Magrone P, Pucci L, Gotti C, Clementi F, De Amici M. Epiboxidine and novel-related analogues: a convenient synthetic approach and estimation of their affinity at neuronal nicotinic acetylcholine receptor subtypes. Bioorg Med Chem Lett. 2008 Aug 15;18(16):4651-4. doi: 10.1016/j.bmcl.2008.07.016. Epub 2008 Jul 10. PMID: 18644719.