Antinociceptive Effects of a Novel α2/α3-Subtype Selective GABAA Receptor Positive Allosteric Modulator.

Pain remains a challenging clinical condition and spinal GABAA receptors are crucial modulators of pain processing. α2/α3-subtype GABAA receptors mediate the analgesic actions of benzodiazepines. Positive allosteric modulators (PAMs) at α2/α3-subtype GABAA receptors may have analgesic potential. Here we report a new selective α2/α3-subtype GABAA receptor PAM in in vitro and in vivo pain assays. KRM-II-81 demonstrated similar efficacy at α1/α2/α3 GABAA receptors and negligible efficacy at α4/α5/α6 GABAA receptors, with α2 and α3-subtypes being 17- and 28-fold more potent than α1 subtypes in HEK-293T cells expressing GABAA receptors with different α subunits. In contrast, KRM-II-18B showed significant efficacy at α1/α2/α3/ α5 subtypes, with similar potency at α1/α2/α3 subtypes. Both PAMs and morphine dose-dependently decreased 0.6% acetic acid- and 0.32% lactic acid-induced writhing. The effects of both PAMs were reversed by the benzodiazepine receptor antagonist flumazenil, confirming their action at the benzodiazepine binding site of GABAA receptors. Both PAMS and morphine all dose-dependently reversed 0.32% lactic acid (but not 0.6% acetic acid) induced suppression of nesting behavior. Acetaminophen, but not the PAMs, reversed acid-depressed locomotor activity. Combined, these findings suggest that KRM-II-81 is a selective α2/α3 subtype GABAA PAM with significant antinociceptive effects in chemical stimulation-induced pain in mice.

Synthesis and Characterization of a Novel γ-Aminobutyric Acid Type A (GABAA) Receptor Ligand That Combines Outstanding Metabolic Stability, Pharmacokinetics, and Anxiolytic Efficacy.

1,4-Benzodiazepines are used in the treatment of anxiety disorders but have limited long-term use due to adverse effects. HZ-166 (2) has been shown to have anxiolytic-like effects with reduced sedative/ataxic liabilities. A 1,3-oxazole KRM-II-81 (9) was discovered from a series of six bioisosteres with significantly improved pharmacokinetic and pharmacodynamic properties as compared to 2. Oxazole 9 was further characterized and exhibited improved anxiolytic-like effects in a mouse marble burying assay and a rat Vogel conflict test.

First In Vivo Testing of Compounds Targeting Group 3 Medulloblastomas Using an Implantable Microdevice as a New Paradigm for Drug Development.

Medulloblastoma is the most common childhood malignant brain tumor. The most lethal medulloblastoma subtype exhibits a high expression of the GABAA receptor α5 subunit gene and MYC amplification. New benzodiazepines have been synthesized to function as α5-GABAA receptor ligands. To compare their efficacy with that of standard-of-care treatments, we have employed a newly developed microscale implantable device that allows for high-throughput localized intratumor drug delivery and efficacy testing. Microdoses of each drug were delivered into small distinct regions of tumors, as confirmed by tissue mass spectrometry, and the local drug effect was determined by immunohistochemistry. We have identified a benzodiazepine derivative, KRM-II-08, as a new potent inhibitor in several α5-GABAA receptor expressing tumor models. This is the first instance of in vivo testing of several benzodiazepine derivatives and standard chemotherapeutic drugs within the same tumor. Obtaining high-throughput drug efficacy data within a native tumor microenvironment as detailed herein, prior to pharmacological optimization for bioavailability or safety and without systemic exposure or toxicity, may allow for rapid prioritization of drug candidates for further pharmacological optimization.

Synthesis of aza and carbocyclic ß-carbolines for the treatment of alcohol abuse. Regiospecific solution to the problem of 3,6-disubstituted ß- and aza-ß-carboline specificity.

A novel two step protocol was developed to gain regiospecific access to 3-substituted ß- and aza-ß-carbolines, 3-PBC (1), 3-ISOPBC (2), ßCCt (3), 6-aza-3-PBC (4) and 6-aza-3-ISOPBC (5). These ß-carbolines (1-3) are potential clinical agents to reduce alcohol self-administration, especially 3-ISOPBC·HCl (2·HCl) which appears to be a potent anti-alcohol agent active against binge drinking in a rat model of maternally deprived (MD) rats. The method consists of two consecutive palladium-catalyzed reactions: a Buchwald-Hartwig amination followed by an intramolecular Heck-type cyclization in high yield.

Recent advances on structural modifications of benzothiazoles and their conjugate systems as potential chemotherapeutics.

INTRODUCTION: Benzothiazole scaffold comprises a bicyclic ring system and is known to exhibit a wide range of biological properties including antimicrobial and anticancer activities. Benzothiazole derivatives have long been therapeutically used for the treatment of various diseases. However, in recent years, 2-arylbenzothiazoles have emerged as an important pharmacophore in the development of antitumor agents. The promising biological profile and synthetic accessibility have been attractive in the design and development of new benzothiazoles and their conjugate systems as potential chemotherapeutics. AREAS COVERED: This review mainly focuses on the structural modifications of benzothiazole scaffold, development of various series of benzothiazoles and their conjugates as new antitumor agents. Furthermore, heterocyclic derivatives bearing benzothiazole moiety and their in vitro as well as in vivo screening, structure-activity relationships (SAR), mechanism, pharmacokinetics, clinical use and their future therapeutic applications are discussed here. EXPERT OPINION: A large number of benzothiazole derivatives discussed here possess potent anticancer activity and can be further developed as drug candidates. Benzothiazole conjugates could also display synergistic effect and still there is a need to use the drug combinations permitting lower dose and development of new generation of drugs. Despite encouraging results that have been observed for their response to tumor in clinical studies, full characterization of their toxicity is further required for their clinical usage as safe drugs for the treatment of cancer. We believe that this review gives a better understanding and scope for future drug design and development of benzothiazole-based compounds to implicate their use in cancer chemotherapy.