Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 12, Issue 1, 2012

Recent years have seen a sea-change in the pharmaceutical industry and the way in which it seeks new medicines. The decline in productivity of the sector, as defined by the number of drugs successfully discovered and developed per R&D spend, has been declining for many years, as documented in numerous studies. (See for example, Scannell et al., Nature Reviews Drug Discovery, 2012, 11, 191 - 200, and references cited therein.) One result has been a somewhat precipitous reduction in the size of the R&D divisions of many large pharmas; many thousands of scientists and others have lost their livelihoods. Many companies have sent large swaths of their discovery work to overseas contract outfits, particularly in China and India. Pharmaceutical research in CNS agents has certainly been affected by these changes, with some organizations essentially getting out of the field entirely. The continued difficulty of seeking new medicines for complex central disorders such as Alzheimer's, Parkinson's, and schizophrenia, and the expense of clinical trials coupled with a high failure rate, has led inexorably to a downsizing of pharma CNS programs in an era of short-term focus on profitability by the larger companies.....

Tuberculosis infection of the central nervous system is a serious and frequently fatal disease. Four drugs have been found to very efficiently inhibit the growth of Mycobacterium tuberculosis and are examined for molecular properties that enable penetration of the blood-brain barrier. Drugs 1, 2, and 3 are aromatic compounds having a single bromine atom in ortho, meta, and para-position, respectively, relative to the hydrazide group (-C(O)NHNH2). A paraposition for bromine enabled the strongest inhibition of Mycobacterium tuberculosis. Drug 4 is a hydrazide derivative of ciprofloxacin. All drugs showed molecular properties suitable for targeting tuberculosis infections of the central nervous system. Drugs 1, 2, 3, 4, and isoniazid showed zero violations of the Rule of 5 and potential capability for oral administration. Values of BB (Cbrain/Cblood) suggested that drugs 1, 2, and 3 will be able to penetrate the brain approximately three times greater than isoniazid. Similarly, the calculated value of BB for drug 4 is comparable to that of isoniazid. Calculated values of polar surface area for drugs 1, 2, 3, and isoniazid indicated a potential rate of intestinal absorption of greater than 75% of drug amount present. The intestinal absorption of drug 4 is predicted to be greater than 50% of total amount present. Drug concentrations necessary for achieving MIC50 for 1, 2, 3, 4, and isoniazid are determined to be 65.9 μg/mL, 29.5 μg/mL, 21.5 μg/mL, 36.4 μg/mL, and 16.7 μg/mL, respectively. The position of the bromine atom within drugs 1, 2, and 3 appears to substantially influence the effectiveness of growth inhibition. These compounds show substantial potential for targeting tuberculosis infections within the central nervous system.

What is the origin of the complex vascular changes that exist in the CNS lesions of Multiple Sclerosis (MS)? From the beginning of the study of the pathological changes in MS in the 19th century, lesions were seen to be associated with veins. On a microscopic level, there have been numerous pathological changes to these vessels including altered structure and permeability, fibrinolysis, iron-related alterations and collagen deposition. Vascular changes in inflammatory conditions outside the CNS are well documented and we hypothesize that angiogenesis (the generation of new blood vessels from existing) is an integral process of lesion development and spread in MS. We demonstrated similar vascular abnormalities in MS and in the animal model, EAE. We measured the increase in angiogenesis-related genes in EAE and review herein the effectiveness of chemical inhibitors of angiogenesis (SU5416, thalidomide and several derivatives). We postulate that interference with angiogenesis provides a suitable non-immunological target for investigation in MS.

Various molecular mechanisms including apoptosis, inflammation, oxidative stress, mitochondrial dysfunction and excitotoxicity have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), though the exact mechanisms have yet to be specified. Furthermore, the underlying restorative molecular mechanisms resulting in neuronal and/or non-neuronal regeneration have to be yet elucidated. Therapeutic agents targeting one or more of these mechanisms to combat either initiation or progression of the disease are under research. Novel treatments including stem cell therapy, growth factors, and gene therapy might prolong survival and delay progression of symptoms. Harnessing the regenerative potential of the central nervous system would be a novel approach for the treatment of motor neuron death resulting from ALS. Endogenous neural replacement, if augmented with administration of exogenous growth factors or with pharmaceuticals that increase the rate of neural progenitor formation, neural migration, and neural maturation could slow the rate of cell loss enough to result in clinical improvement. In this review, we discuss the impact of therapeutic treatment involving stem cell therapy, growth factors, gene therapy, and combination therapy on disease onset and progression of ALS. In addition, we summarize human clinical trials of stem cell therapy, growth factor therapy, and gene therapy in individuals with ALS.

This study highlights conformationally controlled mechanistic aspects of peptide inhibitors for BACE 1. Peptide inhibitors with reduced molecular weight tend to have cyclic conformation leading to reduced interactions with catalytic motif. Conformation plays a major role in determining potency of peptide inhibitors. An attempt has been made at designing lead compound with reduced molecular weight along with proper conformation suitable for active site and retention of specificity analogous to natural substrate. Reduced molecular weight should hopefully lead to enhanced bioavailability.

Regulation of the sleep-waking cycle is complex and involves diverse brain circuits and molecules. On one hand, an interplay among many neuroanatomical and neurochemical systems including acetylcholine, dopamine, noradrenaline, serotonin, histamine, and hypocretin has been shown to control the waking state. On the other hand the sleep-onset is governed by the activity of sleep-promoting neurons placed in the anterior hypothalamus that utilize GABA to inhibit wake-promoting regions. Moreover, brainstem regions inhibited during wakefulness (W) and slow wave sleeps (SWS) become active during rapid eye movement (REM) sleep. Further complexity has been introduced by the recognition of sleep-promoting molecules that accumulate in the brain in prolonged W as well as the physiological role of gene expression during sleep. The sleep-wake cycle is currently undergoing intense research with many new findings leading to new paradigms concerning sleep regulation, brain organization and sleep function. This review provides a broader understanding of our present knowledge in the field of sleep research.

Convolvulus pluricaulis Choisy is a perennial wild herb commonly found on sandy & rocky areas under xerophytic conditions in northern India. It is a reputed drug of ayurveda and reported to posses antioxidant, brain tonic, nervine tonic, laxative and has been used in anxiety, neurosis, epilepsy, insomnia, burning sensation, oedema and urinary disorders. In the present study, methanolic extract of whole plant of Convolvulus pluricaulis Choisy was evaluated for antioxidant activity by using 1, 1-diphenyl-2-picryl- hydrazyl (DPPH) free radical scavenging model and anticonvulsant activity by using maximal electroshock seizure model. In antioxidant activity, ascorbic acid was used as standard agent while results of anticonvulsant studies were compared with phenytoin. Results of antioxidant activity have demonstrated significant free radical scavenging effect for methanolic extract of Convolvulus pluricaulis Choisy. IC50 value of methanolic extract was observed as 41.00μg/ml as compared to 2.03μg/ml of ascorbic acid. Methanolic extract of C. pluricaulis was evaluated for anticonvulsant activity at 250, 500 and 1000mg/kg. Experimental results have shown that at the dose of 500 and 1000mg/kg, C. pluricaulis didn't abolish the hind limb extension, but reduced the mean recovery time from convulsion.

The most common cause of stroke is cerebral ischemia, where blood flow to the brain is interrupted due to a thrombus in a major cerebral artery. Currently, the only therapeutic approach available is thrombolysis. A more recent approach that has started to gain attention is neuroprotection, the ability to prevent neuronal death and enhance endogenous protective mechanisms. Several studies have shown the neuroprotective action of Erythropoietin (EPO). A potential problem in the use of EPO for neurodegenerative disorders is the undesirable erythropoietic side effects. In this context, investigations have been focused to develop derivatives of EPO lacking erythropoietic activity but retaining neuroprotective potential. Low sialic acid-containing EPO (Neuro EPO) is very similar to the one that occurs in the mammalian brain and is rapidly degraded by the liver. Similar neuroprotective effects had been observed with neuro EPO, original recombinant human EPO and EPO variants in ischemia models. Intranasal route could be safe and hematological side effects could be avoided. Neuro EPO that constitutes a new agent has retained the neuroprotective effects without stimulating the EPOR in the bone marrow and can therefore be used without increasing the hematocrit. This review gives a brief introduction to the no hematopoietic effects of EPO, the evidence of neuroprotective effect, the alternatives for obtaining an EPO derivate without hematological side effects and discusses the advantages of nasal administration of Neuro EPO for neuroprotective stroke treatment.