Design, synthesis and evaluation of novel group II metabotropic glutamate receptor allosteric modulators in rodent models of CNS disorders

The Group II metabotropic glutamate (mGlu) receptors include the mGlu2 and mGlu3 receptor subtypes and couple via Gi/o proteins to negatively regulate the activity of adenylyl cyclase. Localization studies suggest that mGlu2 receptors act as presynaptic autoreceptors to modulate release of glutamate, whereas mGlu3 receptors exhibit a broad distribution in the brain and have been shown to be present on astrocytes [1]. Recent findings suggest that neuroadaptations in glutamatergic transmission produced by repeated exposure to drugs of abuse such as cocaine or nicotine are likely to contribute to the maintenance of addictive behaviors including drug use, craving, and relapse to drug taking in humans. Repeated cocaine exposure alters the function of mGlu2 and mGlu3 receptors while nicotine increases glutamatergic neurotransmission by activating excitatory nicotinic acetylcholine (nACh) receptors located on glutamatergic terminals. Brain regions implicated in different aspects of drug abuse and drug dependence display high levels of mGlu2 and mGlu3 receptor binding, suggesting a role for mGlu2/3 receptors in the development of drug dependence and as potential targets for therapeutic agents. We recently reported data on selective mGlu2 receptor positive allosteric modulators (PAMs) in models of drug dependence [2–4]. We now report the design and synthesis of novel, systemically active PAMS that selectively modulate both mGlu2 and mGlu3 receptors. Structure-activity relationship (SAR) data on this series will be described in addition to results from behavioral models of self-administration in rats

Inhibition of Hematopoietic Protein Tyrosine Phosphatase Augments and Prolongs ERK1/2 and p38 Activation

The hematopoietic protein tyrosine phosphatase (HePTP) is implicated in the development of blood cancers through its ability to negatively regulate the mitogen-activated protein kinases (MAPKs) ERK1/2 and p38. Small-molecule modulators of HePTP activity may become valuable in treating hematopoietic malignancies such as T cell acute lymphoblastic leukemia (T-ALL) and acute myelogenous leukemia (AML). Moreover, such compounds will further elucidate the regulation of MAPKs in hematopoietic cells. Although transient activation of MAPKs is crucial for growth and proliferation, prolonged activation of these important signaling molecules induces differentiation, cell cycle arrest, cell senescence, and apoptosis. Specific HePTP inhibitors may promote the latter and thereby may halt the growth of cancer cells. Here, we report the development of a small molecule that augments ERK1/2 and p38 activation in human T cells, specifically by inhibiting HePTP. Structure–activity relationship analysis, <i>in silico</i> docking studies, and mutagenesis experiments reveal how the inhibitor achieves selectivity for HePTP over related phosphatases by interacting with unique amino acid residues in the periphery of the highly conserved catalytic pocket. Importantly, we utilize this compound to show that pharmacological inhibition of HePTP not only augments but also prolongs activation of ERK1/2 and, especially, p38. Moreover, we present similar effects in leukocytes from mice intraperitoneally injected with the inhibitor at doses as low as 3 mg/kg. Our results warrant future studies with this probe compound that may establish HePTP as a new drug target for acute leukemic conditions