Abstract
A series of novel imidazobenzodiazepine analogs of the lead chiral ligand SH-053-2'F-S-CH3 (2), 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 (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.
Highlights
Schizophrenia is one of the most complex central nervous system (CNS) disorders known
Evidence from the ligand-based GABAA receptor (GABAAR) pharmacophore/receptor model and SAR23,35 have indicated that subtle changes in the IBZD substituents affect the BzR/GABA(A)R subtype selectivity dramatically
Based on the results described previously, the ethyl ester 2 was rapidly degraded in the human liver microsomes (HLM), which suggests that modification of the ester might play an essential role in metabolism, as well as efficacy, as compared to the lead compound 2
Summary
Schizophrenia is one of the most complex central nervous system (CNS) disorders known. The symptoms fall into three broad categories: positive symptoms including hallucinations and delusions; negative symptoms such as the blunted affect, social dysfunction and lack of motivation or pleasure in daily life, and cognitive abnormalities. The treatments commonly used to manage positive symptoms are typical and atypical antipsychotic drugs, which target and block the over-activation of dopamine receptors in patients with schizophrenia. The drugs prescribed, to date, only reduce the positive symptoms in the majority of schizophrenia patients. They are often not effective, especially in patients with negative symptoms and cognitive abnormalities.. There is an urgent clinical need for novel drug candidates that can address all aspects of schizophrenia including the alleviation of the negative and cognitive symptoms with decreased side effects
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