The novel hybrid agonist HyNDA-1 targets the D3R-nAChR heteromeric complex in dopaminergic neurons
Articolo
Data di Pubblicazione:
2019
Citazione:
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 May), pp. 154-168. [10.1016/j.bcp.2019.02.019]
Abstract:
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Hybrid Nicotinic Dopaminergic Agonist (HyNDA); Receptor heteromers; Rational drug design; Dopaminergic neurons; Neurotrophic effects
Elenco autori:
C. Matera, F. Bono, S. Pelucchi, G. Collo, L. Bontempi, C. Gotti, M. Zoli, M. De Amici, C. Missale, C. Fiorentini, C. Dallanoce
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