Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 17, Issue 2, 2017

Background: The nicotinic acetylcholine receptor (nAChR) gene family encodes for subunits of acetylcholine gated ion channels. These receptors are expressed widely and have many functions: They mediate excitation at neuro-muscular junctions. Nicotinic Acetylcholine Receptor: In the central nervous system nAChRs have been implicated in memory, cognition, and addiction. And in non-excitatory cells they regulate differentiation, proliferation and inflammatory responses. The CHRNA7 gene encodes for the α7 nAChR subunit that assembles into a homomeric receptor having unusual properties. It is expressed widely and has many functions atypical for nAChRs; specifically, in immune cells α7 is required for the anti-inflammatory effects of acetylcholine and has been implicated in inflammatory autoimmune diseases including Multiple Sclerosis (MS). Interestingly, although, α7 receptors are found at the outer membranes of immune cells, acetylcholine-dependent currents have not been recorded from these cells. Therefore, its mechanism of action in immune cells needs further evaluation. Maturation of α7 into functional ligand-gated channels in the plasma membrane is a complex process shown to depend on the ER-resident chaperone, RIC-3. Therefore, RIC-3 regulates functional expression of α7. RIC-3 like α7 is expressed in immune cells and has been implicated in MS. Thus, RIC-3 may regulate functional expression of α7 in immune cells. Conclusion: In this review we describe effects and mechanism of action of α7 nAChR and RIC-3 in the immune cholinergic system. Elucidating these mechanisms and the regulation of α7 and RIC-3 in the immune cholinergic system can pave the way for novel immunomodulatory agents, or towards extending the application of cholinergic agents.

Background: The α7 nicotinic receptor consists of identical subunits and is one of the most abundant acetylcholine receptors in the mammalian central nervous system. However its expression is also found in the peripheral nervous system as well as in the immune system and various peripheral tissues. Nicotinic Receptors: They are involved in the regulation of several activities ranging from excitatory neurotransmission, the modulation of the release of several neurotransmitters, regulation of neurite outgrowth, and even neuronal survival/death. Its expression is found in brain areas that underlie learning and memory, suggesting their involvement in regulating cognitive functions. The α7-nicotinic receptor has a strategic role during development in regulating molecular pathways activated during neurogenesis. Because of its pleiotropic effects, receptor dysfunction or dysregulated expression is found in pathophysiological conditions of the nervous system including neurodegenerative diseases and neurodevelopmental disorders. Conclusion: Here we review the physiological and pathological roles of alpha-7 nicotinic receptor in different nervous system disorders and the current therapeutic strategies developed to target selectively this receptor for potentiating or reducing its functions.

Background: Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS) characterized by leucocytes infiltration, demyelination, axonal degeneration and neuronal death. Although the etiology of MS is still unkwon, inflammation and autoimmunity are considered to be key players of the disease. Nervous System: The severe alterations affecting the nervous system contribute to the motor and cognitive disabilities and are in large part dependent on severe inflammatory processes active in both central nervous system and immune system. Acetylcholine (ACh) appears to be involved in the modulation of central and peripheral inflammation. Immune cells as well as astrocytes and microglia respond to ACh stimuli by activation of cholinergic receptors. Muscarinic and nicotinic receptors differently contribute to the modulation of immunological and inflammatory processes stimulating pro- and anti-inflammatory cytokines respectively. The role played by ACh in MS is not yet fully understood, although some results point to its involvement in different neurological disorders such as Alzheimer’s disease and schizophrenia. Conclusion: In the present review we summarize the evidence indicating the correlation between nervous system dysfunction in MS, with inflammation and cholinergic system alterations. Experiments performed in MS animal models and analyses on biological fluids from MS patients such as blood, serum and cerebrospinal fluid suggest that cholinergic alterations may contribute to the dysregulated inflammatory processes of MS. Many current therapeutic approaches in MS are based on anti-inflammatory drugs. We also discuss how the use of cholinesterase inhibitors or ACh mimetics may represent a new interesting therapeutic approach in MS.

Background: Thymol (THY), which is a monocyclic monoterpene, found in oil of thyme various other kinds of plants. Until today, although different biological properties of THY have been indicated, its neurological toxicity has never been investigated. Method: In this study, in vitro antiproliferative (by 3-(4,5 dimetylthiazol-2-yl)-2,5 diphenlytetrazolium bromide (MTT) test), genotoxic (by single cell gel electrophoresis (SCGE)) and oxidative effects (by total antioxidant capacity (TAC) and total oxidative status (TOS) analysis) of THY (0-400 mg/L) were assessed on cultured primary rat neurons (CPRNs) and N2a neuroblastoma cells. Results: The obtained data from MTT analysis revealed that THY (only at 400 mg/L) led to significant (p<0.05) decreases of the cell viability in cultured primary rat neurons. And, THY was found to inhibit cell growth in N2a cells at concentrations of 200 and 400 mg/L. Again, DNA damage rates were statistically indifferent (p>0.05) in both treated cell type as compared to control group. The present results also showed that 10, 25 and 50 mg/L of THY application into the cell cultures supported antioxidant capacity in primary rat neurons but not in N2a cells. Conclusion: In a conclusion, these results confirm that THY may have antiproliferative potential against brain tumor cells involving oxidative alteration.

Background: Medicinal chemistry methodologies are presently used to develop multifunctional molecules which simultaneously reduce oxidative stress, excitotoxicity, metal dyshomeostasis, and neuroinflammation that characterize neuropathological conditions, such as Alzheimer’s Disease. Results: Memantine (MEM) derivatives 1-6 were designed and synthesized as novel multifunctional entities with antioxidant and neuroprotective capabilities to manage neurodegenerative diseases, such as Alzheimer's Disease. In vitro neuroprotective studies were performed by using astroglial GL15 cell line to assess antioxidant capability of MEM derivatives 1-6. Conclusion: Our outcomes showed that compounds 1 and 5 (at the concentration of 10 μM), containing as antioxidant portion residues of N-acetyl-Cys-OH and N-acetyl-Cys(Allyl)-OH, respectively, revealed a significant neuroprotective activity against oxidative stress, as assessed by NBT assays.

Background: MRJF4, a novel haloperidol metabolite II prodrug, was obtained through the esterification of the secondary hydroxyl group of haloperidol metabolite II with 4-phenylbutyric acid. The activities of (±)-MRJF4 and its two enantiomers [(+)-MRJF4 and (-)-MRJF4] as tumor specific inducers of pro-apoptotic genes were evaluated on malignant C6 glioma cells. In particular, changes in Nf-ΚB signaling pathway, activity of nitric oxide synthases (NOS), metalloproteinases (MMPs), and membrane adhesion proteins were investigated. Results: IΚBα reduced phosphorylation and iNOS lowered activity could be correlated with the previously demonstrated decreased proliferation and tumor progression of C6 cells upon 24 h of treatment with all the three compounds. Integrin β1 decreased expression, at the same experimental time, seems to support lower C6 cells migrative capability and the consequent reduced invasiveness of these cells upon treatment with (±)-MRJF4 and its enantiomers. Conclusion: These results suggest that this multi-target prodrug and its two enantiomers might be a valuable clinical tool for the treatment of metastatic glioblastoma.

Background: The use of central nervous system (CNS) acting drugs in the management of neuro degenerative and psychiatric problems cannot be overemphasized. Therefore, the chemical structure of piroxicam can be modified to yield new CNS stimulants and depressants that can be of great benefit to man and animals. Methodology: Acetylcholine has Methyl - Oxygen-Oxygen (M-O-O) and Nitrogen (N) functional groups which are structurally related to Sulphur-Oxygen-Oxygen (S-O-O) and Nitrogen (N) of piroxicam that are either methylated or hydrogenated. Each arecoline and nicotine has M-O-O in addition to methylated nitrogen and pyridine ring respectively, making them structurally related to piroxicam. Therefore, when Sulphur of piroxicam is replaced by methyl group, it may likely have muscarinic effects expressed by glandular secretion, gut sedation and vasodepression. Whereas the nitrogen group may be responsible for cholinergic effect in gaglia and striated muscle. Because of the carboxylic functional group (COOH), piroxicam may display depressant effect. Hence C = O, C = N and C = C in piroxicam may change due to biofield treatement. Conclusion: The conversion of piroxicam to central nervous system (CNS) acting drugs may be by desulphation, methylation, dehydrogenation, carboxylation and carbonylation. The would-be synthesized CNS drugs from piroxicam, should have low molecular weight, lipid solubility and low PH.

Background: It is reported that endogenous cannabinoids can cause vasodilation and bradycardia. They have anti-inflammatory effect and protect endothelial cells from injury, therefore they have potential application prospect in the prevention of cardio-cerebrovascular diseases. However, the mechanisms of the neuroprotection mediated by cannabinoid 1 receptors (CB1Rs) have not been uncovered in detail. Methods: Nearly one hundred of new publications relevant to the theme are almost selected from Pubmed. The advanced details associated with the involvement of CB1R in cerebral ischemia as well as cerebral ischemic tolerance are reviewed. Results: Anandamide system is mainly made up of cannabinoid receptors, their endogenous ligands and some related enzymes. The activation of the system mediates various molecular events so that plays a crucial role in the neuroprotection of cerebral ischemia. Increasing evidences suggest that CB1R is one of key molecules that mediate cerebral ischemia and cerebral ischemia tolerance. It is likely to provide an appropriate antioxidant balance by increasing endogenous free radical scavengers and helpful to exert the neuroprotective effects. Moreover, MAPKs, including ERK1/2, c-Jun Nterminal kinase (JNK) and p38MAPK can be recruited and stimulated through a complex signaling networks mediated by CB1R. Considerable evidences have indicated that CB1R was a crucial regulator for ERK1/2 signaling pathway. It is known that PI3K/Akt is a classical signaling pathway and its activation exerts neuroprotective effect via significant promoting cell survival. Glycogen synthase kinase-3β (GSK-3β) is an important downstream target of p-Akt. The PI3K/Akt/GSK-3β signaling pathway mediated by CB1Rs takes an important part in cerebral ischemic injury. PKC and CB1R are found to be abundantly co-expressed in presynaptic nerve endings of brain. There are considerable reports that different PKC isozymes played vital roles respectively in cerebral ischemic injury and preconditioning. The CB1R -mediated activation of PKC can effectively stimulate ischemic tolerance. Conclusion: CB1R played an important part via several signaling pathways in the protection from ischemic stroke and in ischemic tolerance. The involved molecular signaling pathways include ERK1/2, PI3K/Akt/GSK-3β and the translocation and activation of PKC. With the intimate association between CB1R and neuron injuries, to target the receptor will exert neuroprotective effects on cerebral ischemia, which provides wide foreground for a novel therapy target.

Background: The Placebo is defined as an inert substance with a potent therapeutic effect. Its effect is attributed to its psychological and neurobiological effect. Its use in Psychiatric drug practice, drug trials and clinical practice is common, especially in India. Currently there is a debate whether to use it or not as there are ethical, moral and legal issues. Also, its mechanism of action is not known. Discussion: The Indian Psychiatry scenario is muddled in relation to use of placebo in Randomized Controlled Trials or Psychiatric clinical practice. Despite the scepticism associated with this phenomenon physicians get influenced by it. The present article focuses on the reviews done so far on the efficacy and use of placebo and also the points in favour and against the same in drug trials and psychiatric clinical practice. Summary: A number of controversies are associated with this biologically inert substance which has no pharmacological role. Currently in medical sciences many scientific studies have been done solely on placebo. The development in this area may have future implications for further research.

Background: In 2016, the statistical reports stated that Alzheimer is not just memory loss but it kills and has become the 6th leading cause of death. The number of dementia patients is increasing rapidly and expected to rise to 131.5 million by 2050. Still there is not a drug candidate that can cure the cognitive deficits completely. Objective: Series of novel piperazine derivatives have been designed, synthesized and evaluated for cognition enhancing activity. Methods: The synthesized compounds were screened for their in vitro AChE inhibition and reversal of scopolamine induced memory deficit in a passive avoidance stepdown animal model in mice. Enzyme kinetics and molecular docking studies were carried out to elucidate the mechanism of AChE inhibition. Results: All the compounds exhibited excellent IC50 values with potential dual binding site inhibition activity. The IC50 values and inhibition constants of the most promising compounds 1d and 3c were found to be 2.23 μM, 1.05 μM, 14.38 μM and 6.93 μM respectively. They potentially reversed the scopolamine induced memory deficit at a dose of 1.0 mg/kg i.p. in mice. Furthermore, 1d and 3c showed high CNS penetration and brain AChE inhibition in ex vivo experiments. Additionally, significant free radical scavenging activity was determined taking trolox as the standard. Conclusion: Compounds 1d and 3c were emerged as promising of the series and further can be investigated for the future pursuit as drug candidates.