Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 12, Issue 3, 2012

Migraine is a primary headache disorder with an unknown pathophysiology. The growing evidence in recent years indicates migraine being a brain disorder, a sensory dysmodulation, and a system failure of normal sensory processing of the brainstem that involves the vascular tone and pain. At the moment, triptan family and NSAIDs are the first choice drugs for the treatment of acute migraine. There are several prophylactic drugs including the antiepileptic drugs (AEDs), betablockers, and Ca2+ channel blockers that are used for the treatment of migraine. Although many drugs including the triptans, NSAIDs, and others target the peripheral sites of activation, several novel drugs are being developed to target neural sites of action in the central nervous system (CNS). The first trigeminal synapses in the brain stem as well as the ascending and descending pathways and higher brain centers are involved in the transmission of pain and therefore be the main targets of several drugs some of which are in clinical trials. Central sensitization may also aggravate the headache and some drugs tend to alleviate pain by targeting neurotransmitters, receptors, or signalling molecules involved in this phenomenon. This article discusses the CNS acting novel drugs and those that are currently in use for the treatment of migraine.

A new therapeutic approach called Endotherapia (GEMSP) for the treatment of Multiple Sclerosis (MS) is suggested. Endotherapia is the result of an immunopathological strategy addressing chronic incurable diseases with a multifactorial etiology. This approach combines a biomedical evaluation of circulating immunoglobulins directed against specific self-antigens and self-antigens modified by free radicals. GEMSP is a “tailor-made” combination of small molecules (fatty acids, antioxidants, radical scavengers, amino acids) linked to a non-immunogenic linear chain of poly-L.lysine (PLL). Each individual linkage or PLL derivative offers great advantages, such as an increase in the half-life of the active small molecules. GEMSP inhibits brain leukocyte infiltration and abolishes episodes of experimental autoimmune encephalomyelitis. In a clinical trial with 102 MS patients treated with GEMSP Endotherapia, 28% of them showed a worsening of their state; 20% showed a decrease in the progression of the disease; 17% showed disease stabilization; and 35% showed a reversal of the evolution of disease; i.e., an improvement in their disease state. In 72% of the cases, a positive evolution of the state of the MS patients treated with Endotherapia was observed (a decrease or stabilization of disease evolution or an improvement). Endotherapia is very safe and no side-effects were reported for GEMSP. Moreover, GEMSP showed no toxicity either in experimental animals or in humans. It seems that Endotherapia is a promising therapy for MS, with no side-effects, which should be considered in the management of long-term pathologies.

Malignant melanoma is a tumor of the melanocytes of the skin with different types, that can metastasize to many organs including the brain at the advanced stages. Metastasis to brain is most dreadful complication, and at times untreatable as it's noted in the late stages. Therefore, tremendous effort has been made in the past decades to treat metastatic melanoma patients more efficiently. Although chemotherapy is one of the treatment options, it also interferes with all rapidly dividing cells including the non-cancerous cells; therefore one should consider the side effects. As there is lot of evidence that melanoma is immunogenic, a concept of immunotherapy has risen. Immunotherapy uses molecules of the body's own immune system and disrupts the growth of cancer cells has gained a lot of attention in the past two decades. Adoptive cell therapies (ACT), vaccines, viruses, and cytokine administration in immunotherapy stimulate T cells to recognize and destroy the cancer cells. This article is a brief review of various molecules and strategies that are currently used in immunotherapy against malignant melanoma. These include the anti–Cytotoxic T-lymphocyte antigen-4 (CTLA4) antibody, cytokine administration, vaccine therapy, oncolytic viruses, adoptive cell therapy, and inhibitor of STAT3 activation.

The CNS is both source and target of melatonin. This methoxyindole formed in the pineal gland is also produced in other CNS regions and additionally enters the brain by uptake from the circulation as well as via the pineal recess. The mammalian circadian pacemaker, the suprachiasmatic nucleus (SCN), not only controls the pineal, but also receives a feedback information on darkness. Two G protein-coupled melatonin receptors, MT1 and MT2, are responsible for the transduction of many melatonergic actions. High receptor densities are especially found in the SCN, but their presence at lower expression levels in other areas is functionally important. Various metabolites and analogs are formed in the CNS, such as N-acetylserotonin, 5-methoxytryptamine, 5-methoxytryptophol, 5-methoxylated kynuramines, and even 6-sulfatoxymelatonin. The chronobiological effects of melatonin go beyond the resetting of a single circadian oscillator. They contribute to phase relationships between oscillatory subsets and are required for robust rhythm amplitudes. CNS effects of melatonin comprise sleep initiation, antiexcitatory, antiepileptic, antinociceptive, anxiolytic, proneurotrophic, antiinflammatory, antioxidant and other neuroprotective actions. The role as a sleep-promoting compound, which is limited by its short half-life in the circulation, has led to the development of controlled-release formulations and of various synthetic agonists, such as ramelteon, agomelatine, tasimelteon, TIK-301, UCM765 and UCM924. Their differences concerning receptor affinities, preferences for receptor subtypes, and pharmacokinetics are discussed, as well as additional antidepressive actions of agomelatine and TIK-301 based on properties as antagonists of the serotonergic 5-HT2C receptor. Indirect antidepressive effects by melatonergic drugs are largely explained by circadian readjustments.

An emerging new category of therapeutic agents based on ribonucleic acid has emerged and shown very promising in vitro, animal and pre-clinical results, known as small interfering RNAs (siRNAs), microRNAs mimics (miRNA mimics) and their derivates. siRNAs are small RNA molecules that promote potent and specific silencing of mutant, exogenous or aberrant genes through a mechanism known as RNA interference. These agents have called special attention to medicine since they have been used to experimentally treat a series of neurological conditions with distinct etiologies such as prion, viral, bacterial, fungal, genetic disorders and others. siRNAs have also been tested in other scenarios such as: control of anxiety, alcohol consumption, drug-receptor blockage and inhibition of pain signaling. Although in a much earlier stage, miRNAs mimics, anti-miRs and small activating RNAs (saRNAs) also promise novel therapeutic approaches to control gene expression. In this review we intend to introduce clinicians and medical researchers to the most recent advances in the world of siRNA- and miRNA-mediated gene control, its history, applications in cells, animals and humans, delivery methods (an yet unsolved hurdle), current status and possible applications in future clinical practice.

O-1602 is a cannabidiol analogue that does not bind with high affinity to either the cannabinoid CB1 receptor or CB2 receptor. However, there is evidence that O-1602 has significant effects in the central nervous system as well as other parts of the body. Depending upon the model, O-1602 has anti-inflammatory or pronociceptive effects, mediated through a number of distinct receptors. This article reviews the evidence for functional effects of O-1602, particularly in the CNS, and describes its known targets as they relate to these effects. These include the abnormal cannabidiol (Abn- CBD) receptor and GPR55. The GPR18 receptor has been identified with the Abn-CBD receptor, and therefore the evidence that O-1602 also acts at GPR18 is also reviewed. Finally, the evidence that these receptor targets are expressed in the CNS and the phenotypes of cells expressing these targets is discussed, concluding with a discussion of the prospects for O-1602 as a therapeutic agent in the CNS.