Design of novel hexahydropyrazinoquinolines as potent and selective dopamine D3 receptor ligands with improved solubility

We have recently reported hexahydropyrazinoquinolines as a new class of dopamine 3 (D3) receptor ligands with high-affinity to the D3 receptor and excellent selectivity over the closely related D1-like and D2-like receptors. However, our previously reported most potent and selective D3 ligands have poor aqueous solubility, which greatly hinders our in vivo studies aimed at evaluation of their therapeutic potential in animal models. In this study, we wish to report the design, synthesis, and evaluation of a series of new hexahydropyrazinoquinolines as D3 ligands with improved solubility. Among them, compound 4g has a Ki value of 9.7 nM for the D3 receptor and displays a selectivity of >5000 and 466 times over the D1-like and D2-like receptors, respectively. Importantly, the hydrochloride salt form of compound 4g has a good aqueous solubility (>50 mg/mL) and represents a promising D3 ligand for further in vivo evaluations of its therapeutic potential for the treatment of drug abuse, restless legs syndrome, schizophrenia, Parkinson’s disease, and depression.