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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  ( h D 2S R) = 2.8 ± 0.8 nM;  K  i  ( h D 3 R) = 3.0 ± 1.6 nM], promising clogS, clogP, LE ( h D 2S R,  h D 3 R), LipE ( h D 2S R,  h D 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  ( h D 2S R) = 3.2 ± 0.4 nM;  K  i  ( h D 3 R) = 8.5 ± 2.2 nM] revealed clogS, clogP, LE ( h D 2S R,  h D 3 R), LipE ( h D 2S R,  h D 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.

Synthesis, Molecular Properties Estimations, and Dual Dopamine D2 and D3 Receptor Activities of Benzothiazole-Based Ligands