Benzodiazepines (BZD) are a common class of psychoactive medications for the treatment of CNS disorders such as anxiety, epilepsy, neuropathic pain, schizophrenia, depression and other diseases. However, not all patients have a positive response to BZDs, as well as the presence of serious side effects including amnesia, sedation, addiction, ataxia, withdraw and drug resistance. An alpha 2/alpha 3 GABA(A)R subtype-selective ligand Hz-166 (1) was the initial lead imidazobenzodiazepine (IBZ, Zeilhofer et al.) and was found to be anxiolytic in primates (Fischer et al.), an anticonvulsant in rats and mice (Rivas et al.), antihyperalgesia in a pain model (Paul et al.) with no tolerance and less sedative or ataxia effects were observed. However, the ester moiety in 1 was metabolized very rapidly in rodents to its corresponding carboxylic acid, which did not readily pass the blood-brain barrier, which would interfere with ADME TOX in rodents. Therefore, a series of novel ester bioisosteres at C-3 in place of the labile ester group were then designed and synthesized to improve the metabolic stability and achieve enhanced pharmacological effects. Among the series of novel bioisosteres, one of the most promising ligands, a 1,3-oxazole KRM-II-81 (2), was identified as an alpha 2/alpha 3 GABA(A)R subtype-selective ligand very little or no alpha 1 nor alpha 5 efficacy. KRM-II-81 had an excellent metabolic profile in vitro in human, mice, and rat liver microsomes, as compared to the parent ligand 1. The ligand 2 exhibited an anxiolytic effect in a rat Vogel conflict test and a mouse marble-burying assay without rotorod failures. Most recently, the ligand 2 (30 micro M) significantly attenuated the firing rates in human epileptic cortical tissue on a 60 microelectrode array and has a wider margin of effect compared to motor-impairment than diazepam. Moreover, 2 reduces tactile-induced allodynia after CFA-induced pain in rats, and the behavior effects can be attenuated by the BZD receptor antagonist flumazenil. In addition, 2 did not develop tolerance to the antinociceptive effects in rats, nor decreased the respiration rate. The results here indicated that the oxazole 2 could be a potential anxiolytic, anticonvulsant and analgesic for the treatment of anxiety disorders, epilepsy and pain disorders. Recent results will be presented.

Design and synthesis of anxiolytic, anticonvulsant and antinociceptive benzodiazepine/GABA(A)ergic receptor subtype selective ligands as potential nonsedating treatment for anxiety disorders, epilepsy and pain disorders

256th National Meeting (2018)

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