Biochemical Pharmacology | 2019
The novel hybrid agonist HyNDA‐1 targets the D3R‐nAChR heteromeric complex in dopaminergic neurons
Abstract
Graphical abstract Figure. No caption available. &NA; 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 &bgr;2‐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 &bgr;2‐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 (BRET2) 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.