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Synthesis of chiral GABAA receptor subtype selective ligands as potential agents to treat schizophrenia as well as depression.

ABSTRACT: A series of novel imidazobenzodiazepine analogs of the lead chiral ligand SH-053-2'F-S-CH3 (2), an ?2/?3/?5 (Bz)GABA (A)ergic receptor subtype selective ligand, which reversed PCP-induced prepulse inhibition (PPI) of acoustic startle, were synthesized. These chiral (S)-CH3 ligands are targeted for the treatment of schizophrenia and depression. These new ligands were designed by modifying the liable ester functionality in 2 to improve the metabolic stability, cytotoxicity, and activity as compared to 2. Based on the data to date, the most promising ligands are the N-cyclopropyl amide GL-I-55 (8c) and the methyl bioisostere GL-I-65 (9a). The in vitro metabolic stability, cytotoxicity and in vivo locomotor effects are described in this report. Based on these results, 8c and 9a are the most promising for further in vivo pharmacology.

SUBMITTER: Li G 

PROVIDER: S-EPMC7413308 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Synthesis of chiral GABA<sub>A</sub> receptor subtype selective ligands as potential agents to treat schizophrenia as well as depression.

Li Guanguan G   Stephen Michael R MR   Kodali Revathi R   Zahn Nicolas M NM   Poe Michael M MM   Tiruveedhula V V N Phani Babu VVNPB   Huber Alec T AT   Schussman Melissa K MK   Qualmann Krista K   Panhans Cristina M CM   Raddatz Nicholas J NJ   Baker David A DA   Prevot Thomas D TD   Banasr Mounira M   Sibille Etienne E   Arnold Leggy A LA   Cook James M JM  

ARKIVOC : free online journal of organic chemistry 20180311 4

A series of novel imidazobenzodiazepine analogs of the lead chiral ligand SH-053-2'F-<i>S</i>-CH<sub>3</sub> (<b>2</b>), an α2/α3/α5 (Bz)GABA (A)ergic receptor subtype selective ligand, which reversed PCP-induced prepulse inhibition (PPI) of acoustic startle, were synthesized. These chiral (<i>S</i>)-CH<sub>3</sub> ligands are targeted for the treatment of schizophrenia and depression. These new ligands were designed by modifying the liable ester functionality in <b>2</b> to improve the metaboli  ...[more]

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