Bifunctional dopaminergic/nicotinic agonists: novel pharmacological tools to study the D3R/β2*nAChRs heteromeric complex

Bifunctional derivatives have gained a relevant interest in the medicinal chemistry research as potentially innovative therapeutic agents.[1] Indeed, bifunctional drug candidates may concomitantly regulate two biological targets instead of blocking or activating, for example, only one dysfunctional receptor system at a time. As a first contribution in the field, we recently reported the synthesis of new bifunctional derivatives and their affinity/efficacy profiles at D2/non-\u3b17 nAChRs.[2] In this framework, the recent demonstration that D3 dopaminergic and \u3b22-subunit-containing (\u3b22*) nAChRs may assemble in a heteromeric receptor complex [3] has provided the rationale for the investigation of bifunctional compounds targeting such receptor heterodimers. Our study focused on the design and synthesis of novel compounds, which incorporate in a common molecular skeleton two substructures, i.e., the pharmacophoric moiety of the D3 agonist Ropinirole and the fragment of the selective, highly potent \u3b14\u3b22 agonist A-84543 (Figure 1). The synthetic approach and the details of the pharmacological investigation will be illustrated and discussed. Figure 1. Model compounds and target bifunctional derivatives In particular, our findings extend the current understanding of the molecular mechanisms regulating the neuronal plasticity and provide an example of the importance of G protein-coupled receptor and ligand-gated ion channel heteromerization for synaptic efficacy and intrinsic neural properties. Increasing evidence suggests that D2R/D3R agonists may slow the progression of Parkinson\u2019s disease (PD) and that nicotine has neuroprotective effects on dopaminergic neurons. Therefore, the D3/\u3b22*nAChR heteromeric complex may represent a novel therapeutic target for neuroprotection and, accordingly, bifunctional compounds which activate this complex could provide a new pharmacological approach to the treatment of PD. References 1. Wang, M.; Wong, A. H.; Liu, F. Interactions between NMDA and dopamine receptors: a potential therapeutic target. Brain Res. 2012, 1476, 154-163. 2. Matera, C.; Pucci, L.; Fiorentini, C.; Fucile, S.; Missale, C.; Grazioso, G.; Clementi, F.; Zoli, M.; De Amici, M.; Gotti, C.; Dallanoce, C. Bifunctional compounds targeting both D2 and non-\u3b17 nACh receptors: design, synthesis and pharmacological characterization. Eur. J. Med. Chem. 2015, in press. 3. Missale, C. et al., manuscript in preparation