Central Nervous System Agents in Medicinal Chemistry - Volume 6, Issue 2, 2006

The molecular diversity of marine secondary metabolites has been recognized for a number of years, and classic marine-derived excitatory amino acids (EAAs) such as kainic and domoic acid have been indispensable tools in neurobiological research. The recent discovery of the sponge-derived EAA dysiherbaine (DH, 1), a novel di-amino di-acid glutamate analogue with potent convulsant activity, underscores the relatively untapped potential of marine organisms to serve as sources of EAAs with unique structures and activities [1]. DH (1) has a number of pharmacological actions but binds with highest affinity to kainate receptors, a sub-family of non-N-methyl-D-aspartate (non-NMDA)-type GluRs, which are also the molecular targets of other potent EAA convulsants like domoic acid. The high affinity and selectivity of 1 towards certain kainate receptor subtypes made it a useful tool for exploring aspects of the biophysical function of these ion channels [2]. In combination with chemical syntheses and neurophysiological techniques, we have shown that 1 and its structural analogues can serve as unique biophysical and physiological probes of GluR function [3]. Current studies have begun to elucidate the critical moieties on 1 that confer activity and selectivity. We anticipate that 1 will serve as a useful template upon which to build molecules with novel pharmacological actions and potential therapeutic applications. In this review, we describe the chemical, pharmacological and behavioral profile of 1 and closely related analogues, with a particular emphasis on their actions on iGluRs, a family of ligand-gated ion channel critical for excitatory neurotransmission in the mammalian brain.

Signal transduction pathways involving the activation of c-Jun N-terminal kinases (JNK) and p38 mitogenactivated protein kinase (p38MAPK), also called stress-activated protein kinases, have been implicated in many cellular processes such as proliferation, differentiation and death of a variety of cell populations. Growing evidence indicates that these pathways can strongly contribute to the neuronal death associated to neurodegenerative diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis and cerebral ischemia . These kinases can be activated by a variety of toxic stimuli such as oxidative stress, excitotoxicity, inflammatory cytokines through different signalling cascades. Once activated these kinase cascades may induce alterations in the cellular function through transcriptional activity, alterations of cytoskeletal proteins and production and release of inflammatory molecules, all factors highly implicated in the neurodegenerative processes. Thus considerable effort is being addressed to the manipulation of these signal transduction pathways as a potential strategy for therapeutic interventions in neurodegenerative disorders. In this review we will examine the role of JNK and p38MAPK in neurodegeneration and we will illustrate the progresses in the development of inhibitors targeting these stress activated protein kinase pathways as therapeutic approach to neurodegenerative disorders.

Potassium (K+) channels play a critical role in regulating neuronal excitability, a fundamental feature of pain. The opening of K+ channels leads to hyperpolarization of the cell membrane, which results in a decrease of cell excitability. In the nociceptive pathways, K+ channels are involved in a number of processes within the nervous system, including neuronal depolarization, axonal conduction, and neurotransmitter release. As a consequence of the role played by K+ channels in the regulation of the nociceptive system and that K+ channel opening is involved in the antinociception induced by numerous analgesic drugs they have begun to be considered as direct targets for the development of new antinociceptive therapies. A limited number of potential K+ channels have, so far, been identified as targets for the development of antinociceptive therapies. This review considers the potential of selective modulators of KCNQ, KATP, GIRK, Twopore domain K+ channels, or KCa channels as novel therapeutic approaches to pain. Structure-activity relationship (SAR) studies to identify K+ channel selective modulators to target neuroexcitability and pain have, however, been limited to modulators KCNQ channels. The scope of the field of K+ channel modulators is just emerging but demonstrates promise for novel therapeutics in the management of pain.

Platelet-activating factor (PAF) is a phospholipid mediator with widespread biological actions. PAF acts as both an intercellular and intracellular mediator via activation of plasma membrane and intracellular binding sites, respectively. Pharmacological manipulations - using cell site-specific PAF antagonists - can be used to dissect the site of PAF action. Evidence suggests that PAF is a mediator of inflammatory-based pain; PAF elicits, and PAF antagonists attenuate, the inflammatory nociceptive response. For instance, using the biphasic formalin model in rats, we recently demonstrated that systemic, cerebral, and hippocampal administration of PAF antagonists - selective for either intracellular or plasma membrane PAF receptors - decreased the late-phase of the nociceptive response. Interestingly, the site-selective PAF antagonists may act at distinct anatomical locations to alleviate nociception. Thus, PAF may not only at act at distinct anatatomical sites, but at distinct binding sites within these anatomical locales, to modulate the processing of pain of an inflammatory nature. PAF is known to elicit rapid activation of several protein kinase pathways, and to induce mobilization of prostaglandin E2 (PGE2) release. As these mediators are critical signals in nociception, PAF could be an important early mediator of inflammatory-based pain.

The monoamine hypothesis has dominated almost forty years the psychopathology of depression. Yet this has not lead to antidepressants that are significantly more efficacious than the early tri- and tetracyclics from which they have evolved. Alternative hypotheses such as those involving adult neurogenesis or components of the hypothalamic-pituitaryadrenal- axis are either too premature or have not lead to drugs with improved antidepressant activity. Antidepressants may not be perfect, both in terms of efficacy and side effects, however their performance may be improved by making use of so-called augmentation strategies. Augmentation strategies that have potential to hasten and/or improve the therapeutic effect of antidepressants, in particular serotonin reuptake inhibitors, can have different forms. They can be aimed at reducing comorbid symptoms, such as anxiety, or they may be directed to processes that counteract the effect of serotonin reuptake inhibitors. Examples of the latter are those involving 5-HT1A and 5-HT1B autoreceptors, 5-HT 2C receptors and the availability of tryptophan. Another option could be exploring neuropeptide/serotonin interactions. The various augmentation strategies are reviewed in the context of literature data regarding neurobiology and pharmacotherapy of major depression.