AUTHOR=Schübler Moritz , Sadek Bassem , Kottke Tim , Weizel Lilia , Stark Holger 

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

JOURNAL=Frontiers in Chemistry

VOLUME=5

YEAR=2017

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2017.00064

DOI=10.3389/fchem.2017.00064

ISSN=2296-2646

ABSTRACT=<p>Neurleptic drugs, e.g., aripiprazole, targeting the dopamine D<sub>2S</sub> and D<sub>3</sub> receptors (D<sub>2S</sub>R and D<sub>3</sub>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 (<bold>3-20</bold>) was synthesized by applying the bioisosteric approach derived from the selective D<sub>3</sub>Rs ligand <bold>BP-897</bold> (<bold>1</bold>) and its structurally related benz[<italic>d</italic>]imidazole derivative (<bold>2</bold>). Herein, introduction of the benzothiazole moiety was well tolerated by D<sub>2S</sub>R and D<sub>3</sub>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<sub>3</sub>R when compared to that of <bold>1</bold>. Further exploration of different substitution patterns at the benzothiazole heterocycle and the basic 4-phenylpiperazine resulted in the discovery of high dually acting D<sub>2S</sub>R and D<sub>3</sub>R ligands. Moreover, the methoxy substitution at 2-position of 4-phenylpiperazine resulted in significantly (22-fold) increased D<sub>2S</sub>R binding affinity as compared to the parent ligand <bold>1</bold>, and improved physicochemical and drug-likeness properties of ligands <bold>3-11</bold>. However, the latter structural modifications failed to improve the drug-able properties in ligands having un-substituted 4-phenylpiperazine analogs (<bold>12-20</bold>). Accordingly, compound <bold>9</bold> showed in addition to high dual affinity at the D<sub>2S</sub>R and D<sub>3</sub>R [<italic>K</italic><sub>i</sub> (<italic>h</italic>D<sub>2S</sub>R) = 2.8 ± 0.8 nM; <italic>K</italic><sub>i</sub> (<italic>h</italic>D<sub>3</sub>R) = 3.0 ± 1.6 nM], promising clogS, clogP, LE (<italic>h</italic>D<sub>2S</sub>R, <italic>h</italic>D<sub>3</sub>R), LipE (<italic>h</italic>D<sub>2S</sub>R, <italic>h</italic>D<sub>3</sub>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 <bold>10</bold> [<italic>K</italic><sub>i</sub> (<italic>h</italic>D<sub>2S</sub>R) = 3.2 ± 0.4 nM; <italic>K</italic><sub>i</sub> (<italic>h</italic>D<sub>3</sub>R) = 8.5 ± 2.2 nM] revealed clogS, clogP, LE (<italic>h</italic>D<sub>2S</sub>R, <italic>h</italic>D<sub>3</sub>R), LipE (<italic>h</italic>D<sub>2S</sub>R, <italic>h</italic>D<sub>3</sub>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 <bold>3-20</bold> provide clues for the diversity in structure activity relationships (SARs) at the D<sub>2S</sub>R and D<sub>3</sub>R subtypes.</p>