Pragmatic recruitment of memantine as the capping group for the design of HDAC inhibitors: A preliminary attempt to unravel the enigma of glioblastoma.

Hurdled and marred by the notorious nature of glioblastomas (GBM) in terms of resistance to therapy and limited drug delivery into the brain, the anti-GBM drug pipeline is required to be loaded with mechanistically diverse agents. The consideration of HDAC inhibition as a prudent approach to circumvent the resistance issue in GBM spurred us to pragmatically design and synthesizes hydroxamic acids endowed with CNS penetrating ability. By virtue of the blood brain barrier permeability (BBB), memantine was envisioned as an appropriate CAP component for the construction of the HDAC inhibitors. Diverse linkers were stapled for the tetheration of the zinc binding motif with the CAP group to pinpoint an appropriate combination (CAP and linker) that could confer inhibitory preference to HDAC6 isoform (overexpressed in GBM). Resultantly, hydroxamic acid 16 was identified as a promising compound that elicited striking antiproliferative effects against Human U87MG GBM cells as well as TMZ-resistant GBM cells and P1S cells, a concurrent chemo radiotherapy (CCRT)-resistant/patient-derived glioma cell line mediated through preferential HDAC6 inhibition (IC50 = 5.42 nM). Furthermore, 16 exerted cell cycle arrest at G2 phase, induced apoptosis in GBM cells at high concentration and exhibited high BBB permeability. To add on, in-vivo study revealed that the administration of compound 16 prolonged the survival of TMZ-resistant U87MG inoculated orthotopic mice. Overall, the cumulative results indicate that 16 is a tractable CNS penetrant preferential HDAC6 inhibitor that might emerge as a potent weapon against GBM.

The chemistry toolbox of multitarget-directed ligands for Alzheimer's disease.

The discovery and development of multitarget-directed ligands (MTDLs) is a promising strategy to find new therapeutic solutions for neurodegenerative diseases (NDs), in particular for Alzheimer's disease (AD). Currently approved drugs for the clinical management of AD are based on a single-target strategy and focus on restoring neurotransmitter homeostasis. Finding disease-modifying therapies AD and other NDs remains an urgent unmet clinical need. The growing consensus that AD is a multifactorial disease, with several interconnected and deregulated pathological pathways, boosted an intensive research in the design of MTDLs. Due to this scientific boom, the knowledge behind the development of MTDLs remains diffuse and lacks balanced guidelines. To rationalize the large amount of data obtained in this field, we herein revise the progress made over the last 5 years on the development of MTDLs inspired by drugs approved for AD. Due to their putative therapeutic benefit in AD, MTDLs based on MAO-B inhibitors will also be discussed in this review.

Merging memantine and ferulic acid to probe connections between NMDA receptors, oxidative stress and amyloid-ß peptide in Alzheimer's disease.

N-methyl-d-aspartate receptors (NMDAR) are critically involved in the pathogenesis of Alzheimer's disease (AD). Acting as an open-channel blocker, the anti-AD drug memantine preferentially targets NMDAR overactivation, which has been proposed to trigger neurotoxic events mediated by amyloid ß peptide (Aß) and oxidative stress. In this study, we applied a multifunctional approach by conjugating memantine to ferulic acid, which is known to protect the brain from Aß neurotoxicity and neuronal death caused by ROS. The most interesting compound (7) behaved, like memantine, as a voltage-dependent antagonist of NMDAR (IC50 = 6.9 µM). In addition, at 10 µM concentration, 7 exerted antioxidant properties both directly and indirectly through the activation of the Nrf-2 pathway in SH-SY5Y cells. At the same concentration, differently from the parent compounds memantine and ferulic acid alone, it was able to modulate Aß production, as revealed by the observed increase of the non-amyloidogenic sAPPα in H4-SW cells. These findings suggest that compound 7 may represent a promising tool for investigating NMDAR-mediated neurotoxic events involving Aß burden and oxidative damage.

Combination of Memantine and 6-Chlorotacrine as Novel Multi-Target Compound against Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia in the elderly. It is characterized as a multi-factorial disorder with a prevalent genetic component. Due to the unknown etiology, current treatment based on acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate receptors (NMDAR) antagonist is effective only temporary. It seems that curative treatment will necessarily be complex due to the multifactorial nature of the disease. In this context, the so-called "multi-targeting" approach has been established. OBJECTIVES: The aim of this study was to develop a multi-target-directed ligand (MTDL) combining the support for the cholinergic system by inhibition of AChE and at the same time ameliorating the burden caused by glutamate excitotoxicity mediated by the NMDAR receptors. METHODS: We have applied common approaches of organic chemistry to prepare a hybrid of 6-chlorotacrine and memantine. Then, we investigated its blocking ability towards AChE and NMDRS in vitro, as well as its neuroprotective efficacy in vivo in the model of NMDA-induced lessions. We also studied cytotoxic potential of the compound and predicted the ability to cross the blood-brain barrier. RESULTS: A novel molecule formed by combination of 6-chlorotacrine and memantine proved to be a promising multipotent hybrid capable of blocking the action of AChE as well as NMDARs. The presented hybrid surpassed the AChE inhibitory activity of the parent compound 6-Cl-THA twofold. According to results it has been revealed that our novel hybrid blocks NMDARs in the same manner as memantine, potently inhibits AChE and is predicted to cross the blood-brain barrier via passive diffusion. Finally, the MTDL design strategy was indicated by in vivo results which showed that the novel 6-Cl-THA-memantine hybrid displayed a quantitatively better neuroprotective effect than the parent compound memantine. CONCLUSION: We conclude that the combination of two pharmacophores with a synergistic mechanism of action into a single molecule offers great potential for the treatment of CNS disorders associated with cognitive decline and/or excitotoxicity mediated by NMDARs.

Evaluation of [18F]FNM biodistribution and dosimetry based on whole-body PET imaging of rats.

INTRODUCTION: The aim of this work was to study the biodistribution, metabolism and radiation dosimetry of rats injected with [18F]FNM using PET/CT images. This novel radiotracer targeting NMDA receptor has potential for investigation for neurological and psychiatric diseases. METHODS: Free fraction and stability in fresh human plasma were determined in vitro. PET/CT was performed on anesthetized rats. Organs were identified and 3D volumes of interest (VOIs) were manually drawn on the CT in the center of each organ. Time activity curves (TACs) were created with these VOIs, enabling the calculation of residence times. To confirm these values, ex vivo measurements of organs were performed. Plasma and urine were also collected to study in vivo metabolism. Data was extrapolated to humans, effective doses were estimated using ICRP-60 and ICRP-89 dosimetric models and absorbed doses were estimated using OLINDA/EXM V1.0 and OLINDA/EXM V2.0 (which use weighting factors from ICRP-103 to do the calculations). RESULTS: The [18F]FNM was stable in human plasma and the diffusible free fraction was 53%. As with memantine, this tracer is poorly metabolized in vivo. Ex vivo distributions validated PET/CT data as well as demonstrating a decrease of radiotracer uptake in the brain due to anesthesia. Total effective dose was around 6.11 µSv/MBq and 4.65 µSv/MBq for female and male human dosimetric models, respectively. CONCLUSIONS: This study shows that the presented compound exhibits stability in plasma and plasma protein binding very similar to memantine. Its dosimetry shows that it is suitable for use in humans due to a low total effective dose compared to other PET radiotracers.

Triptolide derivatives as potential multifunctional anti-Alzheimer agents: Synthesis and structure-activity relationship studies.

Owning to the promising neuroprotective profile and the ability to cross the blood-brain barrier, triptolide has attracted extensive attention. Although its limited solubility and toxicity have greatly hindered clinical translation, triptolide has nonetheless emerged as a promising candidate for structure-activity relationship studies for Alzheimer's disease. In the present study, a series of triptolide analogs were designed and synthesized, and their neuroprotective and anti-neuroinflammatory effects were then tested using a cell culture model. Among the triptolide derivatives tested, a memantine conjugate, compound 8, showed a remarkable neuroprotective effect against Aß1-42 toxicity in primary cortical neuron cultures as well as an inhibitory effect against LPS-induced TNF-α production in BV2 cells at a subnanomolar concentration. Our findings provide insight into the different pharmacophores that are responsible for the multifunctional effects of triptolide in the central nervous system. Our study should help in the development of triptolide-based multifunctional anti-Alzheimer drugs.

Classics in Chemical Neuroscience: Memantine.

Memantine was the first breakthrough medication for the treatment of moderate to severe Alzheimer's disease (AD) patients and represents a fundamentally new mechanism of action (moderate-affinity, uncompetitive, voltage-dependent, N-methyl-d-aspartate (NMDA) receptor antagonist that exhibits fast on/off kinetics) to modulate glutamatergic dysfunction. Since its approval by the FDA in 2003, memantine, alone and in combination with donepezil, has improved patient outcomes in terms of cognition, behavioral disturbances, daily functioning, and delaying time to institutionalization. In this review, we will highlight the historical significance of memantine to AD (and other neuropsychiatric disorders) as well as provide an overview of the synthesis, pharmacology, and drug metabolism of this unique NMDA uncompetitive antagonist that clearly secures its place among the Classics in Chemical Neuroscience.

An Overview of New Possible Treatments of Alzheimer's Disease, Based on Natural Products and Semi-Synthetic Compounds.

BACKGROUND: Dementias and all related neurodegenerative diseases of the Central Nervous System (CNS) are a current issue arousing a great deal of interest in the international scientific community. This is due to the increasing number of patients suffering from these diseases. These pathologies represent a serious problem, not only concerning the quality of life of the patient, but in addition, the enormous economic efforts that society has to do for their treatment. There are currently a few strategies that are available in order to prevent the progression or to mitigate symptoms of the aforementioned diseases. This consideration is particularly true if we consider the specific pathology of Alzheimer's Disease (AD). METHODS: We performed a literature search for peer-reviewed articles using different databases, such as PubMed or Scopus, and exploiting different keywords and different logical operators. RESULTS: Ninety-eight papers were included in the review. Four papers give an overview of the background of the dementias all over the world. The remaining papers are focused on new possibilities of treatment with natural and semi-synthetic compounds for AD. CONCLUSION: The aim of this review is to give an overview of new and promising natural products and semi-synthetic compounds which could represent a source of "lead compounds" for the development of new potential drugs that could be a valid therapeutic strategy for the treatment of this pathology.

Synthesis and Antioxidant Properties of Novel Memantine Derivatives.

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.

Effect of gabapentin derivates on mechanical allodynia-like behaviour in a rat model of chronic sciatic constriction injury.

A series of mutual prodrugs derived from gabapentin, pregabalin, memantine, venlafaxine were synthesized and their pharmacological properties to treat neuropathic pain were investigated in a rat model of chronic sciatic nerve constriction injury (CCI). In vivo evaluation demonstrated that the mutual prodrugs 2002413A, 2002823A composed of two gabapentins, 2002414 composed of gabapentin and pregabalin were effective in reversal tactile allodynia in CCI rats. The prodrugs 2002413A, 2002414 had no significant influence on the rotarod activity. The result suggest that the prodrugs may be possible candidates for further development.

Fluorine-18 radiolabelling, biodistribution studies and preliminary PET evaluation of a new memantine derivative for imaging the NMDA receptor.

A synthetic method has been established for preparing [18F]1-amino-3-fluoromethyl-5-methyl-adamantane ([18F]AFA). Biodistribution of the radiotracer in mice showed high brain uptake. The peak uptake (3.7% I.D/g organ) for the brain occurred at 30 min after injection. Accumulation of radioactivity in mouse brain was consistent with the known distribution of the NMDA receptors. The binding of [18F]AFA to the phencyclidine (PCP) binding sites of the NMDA receptor complex and the sigma recognition sites in a Rhesus monkey was also examined using positron emission tomography (PET). The regional brain distribution of [18F]AFA was changed by memantine and by (+)-MK-801, indicating competition for the same binding sites. Treatment with haloperidol caused a marked reduction of radioactivity uptake in all the brain regions examined. (-)-Butaclamol, which has pharmacological specificity for sigma sites, did not have any significant effects.

Electrophysiological study, biodistribution in mice, and preliminary PET evaluation in a rhesus monkey of 1-amino-3-[18F]fluoromethyl-5-methyl-adamantane (18F-MEM): a potential radioligand for mapping the NMDA-receptor complex.

The effect of the fluorinated memantine derivative and NMDA receptor antagonist, 1-amino-3-fluoromethyl-5-methyl-adamantane (19F-MEM), at the NMDA receptor ion channel was studied by patch clamp recording. The results showed that 19F-MEM is a moderate NMDA receptor channel blocker. A procedure for the routine preparation of the 18F-labelled analog 18F-MEM has been developed using a two-step reaction sequence. This involves the no-carrier-added nucleophilic radiofluorination of 1-[N-(tert-butyloxy)carbamoyl]-3-(toluenesulfonyloxy)methyl- 5-methyl-adamantane and the subsequent cleavage of the BOC-protecting group using aqueous HCI. The 18F-MEM was obtained in 22 +/- 7% radiochemical yield (decay-corrected to EOB) in a total synthesis time including HPLC purification of 90 min. A biodistribution study after i.v. injection of 18F-MEM in mice showed a fast clearance of radioactivity from blood and relatively high initial uptake in the kidney and in the lung, which gradually decreased with time. The brain uptake was high (up to 3.6% ID/g, 60 min postinjection) with increasing brain-blood ratios: 2.40, 5.10, 6.33, and 9.27 at 5, 30, 60, and 120 min, respectively. The regional accumulation of the radioactivity in the mouse brain was consistent with the known distribution of the PCP recognition site. Preliminary PET evaluation of the radiotracer in a rhesus monkey demonstrated good uptake and prolonged retention in the brain, with a plateau from 35 min onwards p.i. in the NMDA receptor-rich regions (frontal cortex, striata, and temporal cortex). Delineation of the hippocampus, a region known to contain a high density of NMDA receptors, was not possible owing to the resolution of the PET tomograph. The regional brain uptake of 18F-MEM was changed by memantine and by a pharmacological dose of (+)-MK-801, indicating competition for the same binding sites. In a preliminary experiment, haloperidol, a dopamine D2 and sigma receptor antagonist, decreased the binding of 18F-MEM from the brain regions examined, suggesting that binding was also occurring to the sigma recognition sites.