Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 14, Issue 1, 2014

Kynurenine aminotransferase (KAT) isozymes are responsible for catalyzing the conversion of kynurenine (KYN) to kynurenic acid (KYNA), which is considered to play a key role in central nervous system (CNS) disorders, including schizophrenia. The levels of KYNA in the postmortem prefrontal cortex and in the Cerebrospinal fluid (CSF) of schizophrenics are greater than normal brain. A basic strategy to decrease kynurenic acid levels is to promote the inhibition of the biosynthetic KAT isozymes. As there is no crystallographic model for human kynurenine aminotransferase III (KAT III), therefore, homology modeling has been performed based on the Mus musculus kynurenine aminotransferase III crystal structure (PDB ID: 3E2Y) as a template, and the model of the human KAT III was refined and optimized with molecular dynamics simulations. Further evaluation of the model quality was accomplished by investigating the interaction of KAT III inhibitors with the modeled enzyme. Such interactions were determined employing the AutoDock 4.2 program using the MGLTools 1.5.6 package. The most important interactions for the binding of the inhibitors, which are probably also central components of the active site of KAT III, were identified as Ala134, Tyr135, Lys 280, Lys 288, Thr285 and Arg429, which provide hydrogen bond interactions. Additionally, Tyr135 and Arg429 have good electrostatic interactions with inhibitors consistent with these residues also being essential for inhibition of the enzyme activity. We expect that this model and these docking data will be a useful resource for the rational design of novel drugs for treating neuropathologies.

Previous studies have shown that rats subjected to subchronic treatment with nicotine experience changes in COX-2 (a marker of pro-inflammatory systems) and accumulate lipid hydroperoxides (a marker of oxidative stress) in the CNS (CNSMC, 2010; 10:180-206) (hippocampus, frontoparietal cortex and cerebellar cortex). Such changes are specific to each region since each contains different types of neuronal and glial cells with different nicotine receptors. They also differ in animals exposed to a source of oxidative stress, such as D-amphetamine. This paper discusses the changes in other markers of oxidative stress - the isozymes of superoxide dismutase Mn-SOD and Cu/Zn-SOD - in nicotine- and nicotine + D-amphetamine-treated rats. The biochemical and histochemical changes observed were specific to each region (in general very marked in the frontoparietal cortex and the hippocampus but less so in the cerebellar cortex) and each type of neuronal and glial cell. The SODs induced by nicotine may exert a neuroprotective effect via the reduction of oxidative stress. This might be beneficial in the treatment of neurodegenerative diseases. The fact that nicotine did not greatly increase the SODs in the rats treated with D-amphetamine may indicate that the effect of nicotine is partially or totally abolished in situations of oxidative stress. However, since ROS and lipid hydroperoxide levels are also reduced when nicotine is administered to such animals, it could be argued that nicotine is beneficial.

Central nervous system localization of multiple myeloma (CNS-MM) accounts for about 1% of all MM. Treatment is still unsatisfactory. Many treatments have been described in the literature: chemotherapy (CHT), intrathecal therapy (IT), and radiotherapy (RT), with survivals reported between one month and six months. Recent drugs such as the immunomodulatory drugs (IMiDs) and proteasome inhibitors (bortezomib) have changed the treatment of patients with MM, both younger and older, with a significant improvement in response and survival. The activity of new drugs in CNSMM has been reported but is still not well known. Bortezomib does not cross the blood brain barrier (BBB), and IMID’s seem to have only a minimal crossover. The role of novel agents in CNS MM management will be discussed as well as the potential role of other new immunomodulatory drugs (pomalidomide) and proteasome inhibitors that seem to cross the BBB and hold promise into the treatment of this rare and still incurable localization of the disease.

Target of monoamine oxidase inhibitions are considered as the treatment of depressive states and neurodegenerative disorders, including Parkinson’s and Alzheimer’s diseases. Many medicinal chemistry research groups are actively working in this area for the development of most promising selective MAO inhibitors. Many plant isolates also showed remarkable MAO inhibition in recent years. The objective of this review is to identify the major MAO inhibitors secondary metabolites from plants like flavonoids, alkaloids and xanthones class of compounds.

A series of novel substituted quinazolin-4(3H)-one derivatives were synthesized and screened in vivo for their antihypertensive activities. Out of eighteen synthesized compounds, seven i.e. 2a, 2c, 4a, 4d, 5d, 6a & 6b compounds have shown hypotensive effect and produced bradycardia. These compounds have shown better activity than reference drug Prazosin (which acts as anti-hypertensive agent by α1 blocking action). All the compounds have shown ALD50>1000mg/kg with maximum in 2c & 4d (>1200mg/kg).

Convulsion generally occurs as a result of the diminishing concentration of GABA below a threshold level in the brain. This degradation pathway of GABA is catalyzed by the γ-aminobutyric acid amino transferase. The objective of the current study is to propose the binding interaction of 3a, 4-Dihydro-3-H-indeno [1, 2-C] pyrazole-2-Carboxamide/ Carbothioamides anticonvulsant analogs with a three-dimensional structural model of the γ -aminobutyric acid amino transferase. For a flexible type of molecular docking, we proposed that these molecules could successfully bind to the active pocket of the enzyme with good predicted affinities in comparison to standard vigabatrin. In this series, 4b, 4c, 4i, 4f and 4a showed significant binding free energy of -9.64, -9.31, -9.01, -8.99 and -8.29 with predicted inhibitory constant values of 0.086, 0.149, 0.237, 0.257 and 0.831 µM, respectively.

The treatment of brain diseases has been a major challenge since a long time. Although there are several potent drugs, which are highly therapeutic yet their efficiency is marred due to the presence of the Blood Brain Barrier (BBB). The BBB, which is present at the capillary level regulates and monitors the entry of all small and large molecules entering into the brain. Although this barrier is of immense importance to the brain in terms of safety, it becomes a hindrance when it comes to therapy because the drug molecules are unable to reach the brain. Various biomaterial-based strategies are being developed to overcome the BBB and deliver the drug into the brain. These include polymeric nanoparticles, liposomes, solid-lipid nanoparticles (SLNPs), nanogels, implants, etc. This review provides an overview on CNS disorders, BBB, and various delivery strategies available for biologists engaged in translational neuroscience, to target CNS.