Current Medicinal Chemistry - Central Nervous System Agents - Volume 4, Issue 2, 2004

It has been nearly 50 years since Gaddum and Picarelli characterized serotonin M-receptors using an isolated guinea pig ileum preparation; M-receptors, known today as 5-HT3 receptors, are just one of about fifteen different types of serotonin receptors. The discovery of this new class of serotonin receptors evoked a necessity for new ligands to study their pharmacological activity. Today, several 5-HT3 ligands are employed therapeutically in the treatment of emesis, with further potential for the treatment of migraine and numerous central nervous disorders. Using radioligand binding techniques several chemical classes of compounds have been identified and investigated. These studies led to formulation of structure-affinity relationships (SAFIR) and the first two-dimensional pharmacophore model for 5-HT3 receptor ligand binding. Since then, several new SAFIR studies have been conducted and new, more advanced three-dimensional pharmacophore models have been proposed using molecular modeling techniques. In diverse functional assays, the majority of reported 5-HT3 derivatives that meet the established pharmacophore model requirements showed antagonist activity. Structure-activity relationships (SAR) for various classes of 5-HT3 receptor antagonists have been developed. The introduction of m-chlorophenylbiguanide (m-CPBG), a reasonably selective 5-HT3 agonist, called for redefinition of existing pharmacophores. In general, 5-HT3 agonists failed to adhere to 5-HT3 pharmacophore models. This triggered new studies leading to formulation of SAFIR and SAR for agents with 5-HT3 receptor agonist activity. Progress in the development of 5-HT3 agonists and proposed agonist pharmacophore models are reviewed.

The 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMPA) receptors, a subtype of glutamate receptors, are involved in important neuronal functions such as long-term memory. A decrease of the number and activity of these receptors seems to play a role in schizophrenia and in the impairment of cognitive function associated to Alzheimer's disease. Therefore, research has been focused on the development of drugs acting on those receptors, in particular of AMPA receptors positive allosteric modulators. Although agonists have an intrinsic activity, allosteric modulators need the release of glutamate to be active. Therefore, these drugs are expected to exhibit a decreasing risk of toxicity compared to pure agonists. In this article, we review the recent advances in the design of positive allosteric modulators of AMPA receptors.

Antidepressants and antipsychotic drugs comprise the most common groups of prescribed drugs in psychiatry. Despite their efficacy in terms of remission of the primary clinical symptoms, many of them are associated with neurotoxic effects in experimental settings: tricyclic antidepressants and, in particular, typical neuroleptics have been causally linked to neuronal death in vitro that may account for the extrapyramidal effects, e.g. tardive dyskinesia, seen in patients. Here, some of the molecules and signaling cascades underlying these events are reviewed. The article is intended to highlight the shortcomings of current therapeutic agents and thus to encourage the rational design of efficacious, but safer, drugs in the future.

Sleep-related complaints are common in the general population. Prevalence rates are significantly higher among women and the older age groups. About 10% of those experiencing insomnia state that the complaint is chronic. Chronic primary insomnia results from the reaction to an emotional trigger or stressful event, which leads to the further development of sleep-preventing associations. Chronic secondary insomnia is that related to another mental disorder, a neurologic disease, another sleep disorder, a general medical condition, the effect of a drug of abuse or a medication. Sleep disturbances have also been described in pregnancy and during menopause. In patients with chronic primary insomnia nonpharmacological strategies and sleep-promoting medication (e.g. hypnotics) are indicated. In patients with secondary insomnia the underlying disorder needs to be treated appropriately. Currently used hypnotics include benzodiazepine derivatives, the cyclopyrrolone zopiclone, the imidazopyridine zolpidem and the pyrazolopyrimidine zaleplon. In patients with chronic insomnia most hypnotics reduce sleep-onset latency, decrease the number of nocturnal awakenings and reduce the time spent awake. The increase in total sleep time is related to greater amounts of non-rapid eye movement (NREM) sleep. Sleep quality is also improved. Despite consistent effects on sleep-onset latency, zaleplon administration is not associated with significant changes in total sleep time and sleep quality. In contrast to the benzodiazepines and zopiclone, zolpidem and zaleplon do not suppress slow-wave sleep and REM sleep. Sleep laboratory and clinical studies tend to indicate that benzodiazepines are only effective when administered for relatively short periods of time in patients with chronic primary insomnia. Furthermore, a rebound insomnia has been described for short- and intermediate-acting benzodiazepines. No evidence of tolerance or rebound insomnia has been observed in relation to zolpidem or zaleplon administration.

Solitary wasps are known to inject their venoms into insects or spiders and paralyze the prey to feed their larvae. Therefore, the solitary wasp venoms should contain a variety of components acting on nervous systems. Until recently, however, only a few solitary wasp venoms have been studied. We have surveyed bioactive substances in solitary wasp venoms and recently found novel peptide neurotoxins, α- and β-pompilidotoxins (α- and β-PMTXs), in the venoms of pompilid wasps. Chemical and pharmacological characterization of PMTXs revealed that they are small peptides consisting of 13 amino acids with no disulfide bonds. Structure-activity relationship studies showed that the basic amino acid at positions 1, 3 and 12 are essential for regulating the activity. PMTXs facilitate neurotransmission both at invertebrate neuromuscular junctions and in mammalian central synapses by repetitive firings in the presynaptic axons. Whole cell recordings from rat trigeminal ganglion neurons and cultured hippocampal neurons revealed that PMTXs slowed Na+ channel inactivation without affecting kinetics of Na+ channel activation. These effects are similar to those of sea anemone toxins or scorpion toxins, but the PMTXs are distinct from these known toxins in their mode of action. We found region-specific distribution of PMTX-sensitive Na+ channels in the central nervous system by investigating the synaptic transmission in the hippocampal slice preparation and current clamp recordings from hippocampal neurons. Further studies of chimeric mutants of rat brain and heart Na+ channels subunits expressed in HEK cells revealed that two amino acid residues of the extracellular loop of D4S3-S4 in rat brain Na+ channel had been related to the binding site for PMTX. PMTXs would serve as a novel, powerful tool for characterization and classification of Na+ channels.

L-Glutamic acid (glutamate) is a major excitatory amino acid in the nervous system, and it is known that glutamate plays a major role in brain development, affecting neuronal migration, neuronal differentiation, axon genesis, and neuronal survival. Several lines of evidence suggest that a dysfunction in glutamatergic neurotransmission via the Nmethyl- D-aspartate (NMDA) subtype of glutamate receptors might be involved in the pathophysiology of schizophrenia. In this review, we discuss the NMDA receptor hypofunction hypothesis of schizophrenia and the role of glutamate in the action of atypical antipsychotic drugs such as clozapine. In addition, as novel targets for therapeutic drugs for the treatment of schizophrenia, we focus on the glycine sites on NMDA receptors, metabotropic glutamate (mGlu) receptors, and AMPA receptors. This review covers known information about agonists for the glycine site on NMDA receptors, the glycine transporter inhibitors, the mGlu II receptor agonists, and the allosteric modulators of AMPA receptors.