Synthesis, Molecular Properties Estimations, and Dual Dopamine D(2) and D(3) Receptor Activities of Benzothiazole-Based Ligands

Neurleptic drugs, e.g., aripiprazole, targeting the dopamine D(2S) and D(3) receptors (D(2S)R and D(3)R) 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 D(3)Rs ligand BP-897 (1) and its structurally related benz[d]imidazole derivative (2). Herein, introduction of the benzothiazole moiety was well tolerated by D(2S)R and D(3)R 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 D(3)R 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(2S)R and D(3)R ligands. Moreover, the methoxy substitution at 2-position of 4-phenylpiperazine resulted in significantly (22-fold) increased D(2S)R 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(2S)R and D(3)R [K(i) (hD(2S)R) = 2.8 ± 0.8 nM; K(i) (hD(3)R) = 3.0 ± 1.6 nM], promising clogS, clogP, LE (hD(2S)R, hD(3)R), LipE (hD(2S)R, hD(3)R), 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(2S)R) = 3.2 ± 0.4 nM; K(i) (hD(3)R) = 8.5 ± 2.2 nM] revealed clogS, clogP, LE (hD(2S)R, hD(3)R), LipE (hD(2S)R, hD(3)R) 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(2S)R and D(3)R subtypes.