A new D2 dopamine receptor agonist allosterically modulates A2A adenosine receptor signalling by interacting with the A2A/D2 receptor heteromer

Since the development of new molecules able to target A2A/D2 dimers may represent an attractive tool for innovative pharmacological therapy, we also identified a new small molecule, 3-(3,4-dimethylphenyl)-1-(2-piperidin-1-yl)ethyl)piperidine (compound 1), full agonist of D2DR and modulator of A2A-D2 receptor dimer. This compound was able to negatively modulate A2AAR binding properties and functional responsiveness in a manner comparable to classical D2R agonists. In contrast to classical agonists, compound 1 led to conformational changes in the quaternary structure in D2DR homomers and heteromers and induced A2AAR/D2DR co-internalization. These results suggest that compound 1 exerts a high control of the function of heteromers and could represent a starting point for the development of new drugs targeting A2AAR/D2 DR heteromers.