1‑[3-(4-Butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1) as a Model for the Rational Design of a Novel Class of Brain Penetrant Ligands with High Affinity and Selectivity for Dopamine D₄ Receptor

In the present article, the M₁ mAChR bitopic agonist 1-[3-(4-butylpiperidin-1-yl)­propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 1) has been demonstrated to show unexpected D₄R selectivity over D₂R and D₃R and to behave as a D₄R antagonist. To better understand the structural features required for the selective interaction with the D₄R and to obtain compounds unable to activate mAChRs, the aliphatic butyl chain and the piperidine nucleus of 1 were modified, affording compounds 2–14. The 4-benzylpiperidine 9 and the 4-phenylpiperazine 12 showed high D₄R affinity and selectivity not only over the other D₂-like subtypes, but also over M₁–M₅ mAChRs. Derivative 12 was also highly selective over some selected off-targets. This compound showed biased behavior, potently and partially activating G_i protein and inhibiting β-arrestin2 recruitment in functional studies. Pharmacokinetic studies demonstrated that it was characterized by a relevant brain penetration. Therefore, 12 might be a useful tool to better clarify the role played by D₄R in disorders in which this subtype is involved.