In this paper, we designed, synthesized and tested a small set of three new derivatives potentially targeting the D3R-nAChR heteromer, a receptor complex recently identified and characterized as the molecular entity that, in dopaminergic neurons, mediates the neurotrophic effects of nicotine. By means of a partially rigidified spacer of variable length, we incorporated in the new compounds (1a–c) the pharmacophoric substructure of a known β2-subunit-containing nAChR agonist (A-84543) and that of the D2/D3R agonist drug ropinirole. All the compounds retained the ability to bind with high affinity both β2-subunit-containing nAChR and D3R. Compound 1a, renamed HyNDA-1, which is characterized by the shortest linker moiety, was the most interesting ligand. We found, in fact, that HyNDA-1 significantly modulated structural plasticity on both mice and human dopaminergic neurons, an effect strongly prevented by co-incubating this ligand with either nAChR or D3R antagonists. Moreover, the neurotrophic effects of HyNDA-1 were specifically lost by disrupting the complex with specific interfering peptides. Interestingly, by using the Bioluminescence Resonance Energy Transfer 2 (BRET 2 ) assay in HEK-293 transfected cells, we also found that HyNDA-1 has the ability to increase the affinity of interaction between nAChR and D3R. Overall, our results indicate that the neurotrophic effects of HyNDA-1 are mediated by activation of the D3R-nAChR heteromeric complex specifically expressed on dopaminergic neurons.
The novel hybrid agonist HyNDA-1 targets the D3R-nAChR heteromeric complex in dopaminergic neurons / C. Matera, F. Bono, S. Pelucchi, G. Collo, L. Bontempi, C. Gotti, M. Zoli, M. De Amici, C. Missale, C. Fiorentini, C. Dallanoce. - In: BIOCHEMICAL PHARMACOLOGY. - ISSN 0006-2952. - 163(2019), pp. 154-168.
|Titolo:||The novel hybrid agonist HyNDA-1 targets the D3R-nAChR heteromeric complex in dopaminergic neurons|
MATERA, CARLO (Primo)
DALLANOCE, CLELIA MARIANGIOLA LUISA (Ultimo) (Corresponding)
|Parole Chiave:||Hybrid Nicotinic Dopaminergic Agonist (HyNDA); Receptor heteromers; Rational drug design; Dopaminergic neurons; Neurotrophic effects|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
Settore BIO/14 - Farmacologia
|Data di pubblicazione:||2019|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.bcp.2019.02.019|
|Appare nelle tipologie:||01 - Articolo su periodico|