Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 7, Issue 3, 2007

Conventional antipsychotic drugs, which have been used for a half century to treat a range of major psychiatric disorders like schizophrenia, are being replaced by modern “atypical antipsychotics”. Although the term “atypical” has been applied broadly to antipsychotic drugs marketed in the past decade, these newer drugs are strikingly heterogeneous in chemical, pharmacological, and clinical points of view. Recently, much attention has been directed to partial dopamine receptor agonists as promising atypical antipsychotics with properties of “dopamine system stabilizers”, which behave either as agonists or antagonists depending on the functional state of the dopamine receptors. Aripiprazole (OPC-14597) is the first and unique antipsychotic drug with such pharmacological properties commercially available in US, Europe, and most recently in Japan. In the present article, the term “atypicality” is critically revisited, and the place of partial dopamine receptor agonists in atypical antipsychotics is overviewed with special reference to the intrinsic activities appropriate for treating the schizophrenic patients with greatest efficacy and least liability of adverse effects such as extrapyramidal symptoms.

Amphotericin B remains an important choice for central nervous system (CNS) fungal infections, although its adverse effects have limited its use, especially nephratoxicity. New formulations of amphotericin B, new azoles and echinocandins have been developed for clinical use in the past decade. However, high mortality is associated with CNS fungal infections, especially those due to filamentous fungi. Mortality risk of cerebral mucormycosis approaches 100% although amphotericin B and neurosurgical intervention are used. Use of voriconazole has improved prognosis of cerebral aspergillosis. However, the mortality risk of the disease remains 70%. The antifungal therapy of minimum of CNS fungal infections due to yeast fungi and endemic fungi, such as Candida spp. Cryptococcus neoformans, Coccidioides immitis, Histoplasma capsulatum, and Blastomyces dermatitidis has been standardized. However, high mortality and increase of CNS fungal infections resistant to standard therapy is waiting for utility of new antifungal options. The treatment of CNS fungal infections due to less common and newly emerging fungi, such as Acremonium species, Fusarium species, Pacilomyces species, Trichoderma species, Trichosporon species, Zygomycetes, and Phaeohyphomectes is challenging and no well-designed studies have been carried out, the available data are based on case reports. In conclusion, the prognosis of CNS fungal infections is not good. Early diagnosis, appropriate use of antifungal agents and management of underlying disease, in combination with neurosurgical intervention may improve the outcome.

Idiopathic Parkinson's disease (PD) is characterized by a Lewy body-degeneration of presynaptic nigrostriatal dopaminergic neurons. This degeneration can be visualized by nuclear medicine methods, primarily by FP-CIT SPECT: Fluoropropyl-Carbomethoxy-Iodophenyl-Tropan (FP-CIT), marked by radioactive 123iodine, binds to dopamine reuptake transporters at the presynaptic membrane of the nigral dopaminergic neuron. Due to its fast and highly affine binding (Ki = 3.1 nM) to dopamine transporters, FP-CIT SPECT is the most favored nuclear medicine method to support the diagnosis of PD. FP-CIT SPECT shows a high sensitivity concerning PD (95%-100%), a high specificity against essential tremor (100%), but a rather low specificity against atypical parkinsonian syndromes. FP-CIT SPECT reflects the nigrostriatal dopaminergic function in PD, since FP-CIT SPECT correlates significantly with the motor part of the UPDRS (Unified Parkinson´s disease rating scale) score. Recently we correlated the nigrostriatal FP-CIT uptake with parkinsonian cardinal symptoms hypokinesia, rigidity, resting tremor and postural tremor: nigrostriatal FP-CIT uptake correlated significantly inversely with the extent of hypokinesia and rigidity, but there was no correlation between FP-CIT uptake versus resting or postural tremor. These findings correspond to clinical observations that hypokinesia and rigidity - rather than resting or postural tremor - respond well to dopaminergic drugs. Accordingly histopathological studies disclosed a Lewy bodydegeneration not only of dopaminergic neurons but also of serotoninergic and cholinergic nuclear grays. Nuclear medicine examinations of further cerebral transmitter systems - primarily of the serotoninergic and the cholinergic system - seem to be necessary to understand the pathophysiology of resting and postural tremor in PD.

Multiple lines of evidence suggest that hypofunction of glutamatergic neurotransmission via N-methyl-Daspartate (NMDA) receptors might be implicated in the pathophysiology of schizophrenia. The NMDA receptor hypofunction hypothesis of schizophrenia suggests that increasing NMDA receptor function via pharmacological manipulation could provide a potential new strategy for the management of schizophrenia. Currently, the glycine modulatory sites on NMDA receptors present the most attractive therapeutic targets for the treatment of schizophrenia. One means of enhancing NMDA receptor neurotransmission is to increase the availability of the obligatory co-agonist glycine at modulatory sites through the inhibition of glycine transporter-1 (GlyT-1) on glial cells. With the aim of treating schizophrenia, a number of pharmaceutical industries have developed novel and selective GlyT-1 inhibitors, and recent studies have demonstrated that the GlyT-1 inhibitor sarcosine (N-methyl glycine) could be a potential drug. The present review considers GlyT-1 inhibitors as novel drugs for the treatment of schizophrenia.

The development of CNS drugs has been the most challenging task in drug design. Only an abysmal one percent of nervous system drugs tested in human clinical trials ever reach market. This is largely attributable to the difficulties in both identifying appropriate targets and in understanding the toxicology, pharmacology, and pharmaceutical properties of therapeutic compounds. Pesticides have not attracted much attention in the field of CNS drug design. However, the toxicological and molecular actions of certain pesticides, such as chlorpyrifos and pyrethroids, have been well studied. Furthermore, recent epidemiological data have provided important insights into the actions of pesticides in the human brain. Therefore, in this review we seek to examine and summarize the toxicological and molecular actions of common pesticides, organophosphates and pyrethroids. We will also summarize and compare the effects of common pesticides on the neurological functions in animals and in humans. Common pesticides have been shown to act on molecular targets such as the serotonin receptors, brain-derived neurotrophic factor (BDNF), and the transcription factor CREB. Likewise, pesticides can affect multiple neurological functions, such as motor coordination, habituation, attention, cognition, and psychomotor development. A comprehensive review of the toxicological and molecular roles of pesticides in the CNS might provide insights into the actions of CNS agents.

A series of Schiff bases of menthone has been synthesized using an appropriate synthetic route and characterized using Thin Layer Chromatography and spectral analysis. The synthesized compounds were evaluated for anticonvulsant activity against maximal electro shock (MES) and strychnine induced seizures model in rats. The neurotoxicity and behavioral depressant studies were also carried out using rotorod and tail suspension methods. Results obtained show that, 84% of the compounds afforded significant protection in the MES screen whereas none of them found to be active in strychnine induced seizures. Schiff base with napthyl amine was found to be most active in the series showing activity in the dose of 10 mg/kg in MES test. Majority of the compounds were found to be active in behavioral depressant screening.

Mitochondria are key players in the energetic metabolism, providing energy for almost every cellular process, playing also a central role in the maintenance of normal cellular function. The brain has a high energy demand; hence neurons are especially susceptible to disturbances in oxygen and nutrient availability. Such disturbances, as observed in pathologies such as ischemia/reperfusion or stroke, can represent an insult with irreversible consequences to cell viability. Mitochondrial dysfunction resulting from pathological events represents a serious threat to cellular viability. Since mitochondria are tightly related with a variety of cellular processes, the loss of mitochondrial function frequently represents a point of no return towards cell death. In this aspect, mitochondria can also play an important role in the decision of cellular fate - apoptosis versus necrosis. The search for compounds aiming at neuroprotection through the preservation of mitochondrial function might prove to be a suitable therapeutic approach for the treatment of neurodegenerative diseases. Examples of such molecules are phenolic compounds, which can be found in natural sources such as in plant extracts. Phenolics present in Hypericum perforatum are endowed with strong antioxidant and neuroprotective properties. In fact, the observed protection is suggested to be, at least in part, mediated through mitochondria-based effects, indicating a potential application for the use of such compounds or extracts in neuroprotection.