Synthesis, molecular properties estimations, and dual dopamine D₂ and D₃ receptor activities of benzothiazole-based ligands

Neurleptic drugs, e.g., aripiprazole, targeting the dopamine D_2S and D₃ receptors (D_2SR and D₃R) in the central nervous system are widely used in the treatment of several psychotic and neurodegenerative diseases. Therefore, a new series of benzothiazole-based ligands (3-20) was synthesized by applying the bioisosteric approach derived from the selective D₃Rs ligand BP-897 (1) and its structurally related benz[d]imidazole derivative (2). Herein, introduction of the benzothiazole moiety was well tolerated by D_2SR and D₃R binding sites leading to antagonist affinities in the low nanomolar concentration range at both receptor subtypes. However, all novel compounds showed lower antagonist affinity to D₃R when compared to that of 1. Further exploration of different substitution patterns at the benzothiazole heterocycle and the basic 4-phenylpiperazine resulted in the discovery of high dually acting D_2SR and D₃R ligands. Moreover, the methoxy substitution at 2-position of 4-phenylpiperazine resulted in significantly (22-fold) increased D_2SR binding affinity as compared to the parent ligand 1, and improved physicochemical and drug-likeness properties of ligands 3-11. However, the latter structural modifications failed to improve the drug-able properties in ligands having un-substituted 4-phenylpiperazine analogs (12-20). Accordingly, compound 9 showed in addition to high dual affinity at the D_2SR and D₃R [K_i (hD_2SR) = 2.8 ± 0.8 nM; K_i (hD₃R) = 3.0 ± 1.6 nM], promising clogS, clogP, LE (hD_2SR, hD₃R), LipE (hD_2SR, hD₃R), and drug-likeness score values of -4.7, 4.2, (0.4, 0.4), (4.4, 4.3), and 0.7, respectively. Also, the deaminated analog 10 [K_i (hD_2SR) = 3.2 ± 0.4 nM; K_i (hD₃R) = 8.5 ± 2.2 nM] revealed clogS, clogP, LE (hD_2SR, hD₃R), LipE (hD_2SR, hD₃R) and drug-likeness score values of -4.7, 4.2, (0.4, 0.4), (3.9, 3.5), and 0.4, respectively. The results observed for the newly developed benzothiazole-based ligands 3-20 provide clues for the diversity in structure activity relationships (SARs) at the D_2SR and D₃R subtypes.