Synthesis and biological investigations of dopaminergic partial agonists preferentially recognizing the D4 receptor subtype

Aminomethyl-substituted biaryls bearing a pyrazole or triazole moiety were synthesized and investigated for dopamine and serotonin receptor binding. The N-arylpyrazoles 3b,f,g and 4 revealed Ki values in the subnanomolar range (0.28–0.70 nM) for the dopamine D4 receptor subtype. Employing both mitogenesis and GTPγS assays, ligand efficacy was evaluated indicating partial agonist properties. Interestingly, the tetrahydropyrimidine 4 (FAUC 2020) displayed significant intrinsic selectivity for D2long over D2short.