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) 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.