Discovery of a Novel Multitarget Analgesic Through an In Vivo-Guided Approach.

Pain is a complex condition influenced by peripheral, central, immune, and psychological factors. Multitarget approaches offer a more effective and safer alternative to single-target analgesics by enhancing efficacy, reducing side effects, and minimizing tolerance. This study aimed to identify a novel multitarget analgesic with improved pharmacological properties.

Discovery of RC-752, a Novel Sigma-1 Receptor Antagonist with Antinociceptive Activity: A Promising Tool for Fighting Neuropathic Pain.

Neuropathic pain (NP) is a chronic condition resulting from damaged pain-signaling pathways. It is a debilitating disorder that affects up to 10% of the world's population. Although opioid analgesics are effective in reducing pain, they present severe risks; so, there is a pressing need for non-opioid pain-relieving drugs.

Discovery of potent indazole-based human glutaminyl cyclase (QC) inhibitors as Anti-Alzheimer's disease agents.

The toxic pyroglutamate form of amyloid-β (pE-Aβ) is important for the pathogenesis of early Alzheimer's disease (AD); therefore, reducing pE-Aβ by inhibiting glutaminyl cyclase (QC) provides a promising strategy for developing disease-modifying AD drugs. In this study, potent and selective QC inhibitors with desirable drug-like properties were discovered by replacing the 3,4-dimethoxyphenyl group in a QC inhibitor with a bioisosteric indazole surrogate. Among them, 3-methylindazole-6-yl and 3-methylindazole-5-yl derivatives with an N-cyclohexylurea were identified as highly potent inhibitors with IC values of 3.

-GlcNAcylation ameliorates the pathological manifestations of Alzheimer's disease by inhibiting necroptosis.

-GlcNAcylation (-linked β--acetylglucosaminylation) is notably decreased in Alzheimer's disease (AD) brain. Necroptosis is activated in AD brain and is positively correlated with neuroinflammation and tau pathology. However, the links among altered -GlcNAcylation, β-amyloid (Aβ) accumulation, and necroptosis are unclear.

Discovery of Benzopyridone-Based Transient Receptor Potential Vanilloid 1 Agonists and Antagonists and the Structural Elucidation of Their Activity Shift.

Among a series of benzopyridone-based scaffolds investigated as human transient receptor potential vanilloid 1 (TRPV1) ligands, two isomeric benzopyridone scaffolds demonstrated a consistent and distinctive functional profile in which 2-oxo-1,2-dihydroquinolin-5-yl analogues (e.g., ) displayed high affinity and potent antagonism, whereas 1-oxo-1,2-dihydroisoquinolin-5-yl analogues (e.

Discovery of Nonpungent Transient Receptor Potential Vanilloid 1 (TRPV1) Agonist as Strong Topical Analgesic.

Paradoxically, some TRPV1 agonists are, at the organismal level, both nonpungent and clinically useful as topical analgesics. Here, we describe the scaled-up synthesis and characterization in mouse models of a novel, nonpungent vanilloid. Potent analgesic activity was observed in models of neuropathic pain, and the compound blocked capsaicin induced allodynia, showing dermal accumulation with little transdermal absorption.

Discovery of Conformationally Restricted Human Glutaminyl Cyclase Inhibitors as Potent Anti-Alzheimer's Agents by Structure-Based Design.

Alzheimer's disease (AD) is an incurable, progressive neurodegenerative disease whose pathogenesis cannot be defined by one single element but consists of various factors; thus, there is a call for alternative approaches to tackle the multifaceted aspects of AD. Among the potential alternative targets, we aim to focus on glutaminyl cyclase (QC), which reduces the toxic pyroform of β-amyloid in the brains of AD patients. On the basis of a putative active conformation of the prototype inhibitor , a series of N-substituted thiourea, urea, and α-substituted amide derivatives were developed.

Structure-activity relationship investigation of Phe-Arg mimetic region of human glutaminyl cyclase inhibitors.

Glutamyl cyclase (QC) is a promising therapeutic target because of its involvement in the pathogenesis of Alzheimer's disease. In this study, we developed novel QC inhibitors that contain 3-aminoalkyloxy-4-methoxyphenyl and 4-aminoalkyloxyphenyl groups to replace the previously developed pharmacophore. Several potent inhibitors were identified, showing IC values in a low nanomolar range, and were further studied for in vitro toxicity and in vivo activity.

Potent human glutaminyl cyclase inhibitors as potential anti-Alzheimer's agents: Structure-activity relationship study of Arg-mimetic region.

Pyroglutamate-modified amyloid β peptides (pGlu-Aβ) are highly neurotoxic and promote the formation of amyloid plaques. The pGlu-Aβ peptides are generated by glutaminyl cyclase (QC), and recent clinical studies indicate that QC represents an alternative therapeutic target to treat Alzheimer's disease (AD). We have previously developed a series of QC inhibitors with an extended pharmacophoric scaffold, termed the Arg-mimetic D-region.

Discovery of an Orally Bioavailable Benzofuran Analogue That Serves as a β-Amyloid Aggregation Inhibitor for the Potential Treatment of Alzheimer's Disease.

We developed an orally active and blood-brain-barrier-permeable benzofuran analogue (8, MDR-1339) with potent antiaggregation activity. Compound 8 restored cellular viability from Aβ-induced cytotoxicity but also improved the learning and memory function of AD model mice by reducing the Aβ aggregates in the brains. Given the high bioavailability and brain permeability demonstrated in our pharmacokinetic studies, 8 will provide a novel scaffold for an Aβ-aggregation inhibitor that may offer an alternative treatment for AD.

Production of transgenic pig as an Alzheimer's disease model using a multi-cistronic vector system.

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with memory loss and cognitive impairments. An AD transgenic (Tg) pig model would be useful for preclinical testing of therapeutic agents. We generated an AD Tg pig by somatic cell nuclear transfer (SCNT) using a multi-cistronic vector that harbored three AD-related genes with a total of six well-characterized mutations: hAPP (K670N/M671L, I716V, and V717I), hTau (P301L), and hPS1 (M146V and L286P).

Discovery of Potent Human Glutaminyl Cyclase Inhibitors as Anti-Alzheimer's Agents Based on Rational Design.

Glutaminyl cyclase (QC) has been implicated in the formation of toxic amyloid plaques by generating the N-terminal pyroglutamate of β-amyloid peptides (pGlu-Aβ) and thus may participate in the pathogenesis of Alzheimer's disease (AD). We designed a library of glutamyl cyclase (QC) inhibitors based on the proposed binding mode of the preferred substrate, Aβ. An in vitro structure-activity relationship study identified several excellent QC inhibitors demonstrating 5- to 40-fold increases in potency compared to a known QC inhibitor.

6-Phenoxy-2-phenylbenzoxazoles, novel inhibitors of receptor for advanced glycation end products (RAGE).

Receptor for advanced glycation end products (RAGE) is known to be involved in the transportation of amyloid β (Aβ) peptides and causes the accumulation of Aβ in the brain. Moreover, recent studies suggest that the interactions between RAGE and Aβ peptides may be the culprit behind Alzheimer's disease (AD). Inhibitors of the RAGE-Aβ interactions would not only prevent the accumulation of toxic Aβ in the brain, and but also block the progress of AD, therefore, have the potential to provide a 'disease-modifying therapy'.

Pyrazole-5-carboxamides, novel inhibitors of receptor for advanced glycation end products (RAGE).

In an effort to develop novel inhibitors of receptor for advanced glycation end products (RAGE) for the treatment of Alzheimer's disease, a series of pyrazole-5-carboxamides were designed, synthesized and biologically evaluated. Analyses of the extensive structure-activity relationship (SAR) led us to identify a 4-fluorophenoxy analog (40) that exhibited improved in vitro RAGE inhibitory activity and more favorable aqueous solubility than the parent 2-aminopyrimidine, 1. Surface plasmon resonance (SPR) and molecular docking study strongly supported the RAGE inhibitory activity of pyrazole-5-carboxamides.

Mesenchymal stem cells enhance autophagy and increase β-amyloid clearance in Alzheimer disease models.

Current evidence suggests a central role for autophagy in Alzheimer disease (AD), and dysfunction in the autophagic system may lead to amyloid-β (Aβ) accumulation. Using in vitro and in vivo AD models, the present study investigated whether mesenchymal stem cells (MSCs) could enhance autophagy and thus exert a neuroprotective effect through modulation of Aβ clearance In Aβ-treated neuronal cells, MSCs increased cellular viability and enhanced LC3-II expression compared with cells treated with Aβ only. Immunofluorescence revealed that MSC coculture in Aβ-treated neuronal cells increased the number of LC3-II-positive autophagosomes that were colocalized with a lysosomal marker.

Two β-strands of RAGE participate in the recognition and transport of amyloid-β peptide across the blood brain barrier.

Amyloid-β (Aβ) peptide is central to the development of brain pathology in Alzheimer disease (AD) patients. Association with receptors for advanced glycation end-products (RAGE) enables the transport of Aβ peptide from circulating blood to human brain, and also causes the activation of the NF-κB signaling pathway. Here we show that two β-strands of RAGE participate in the interaction with Aβ peptide.

Ligand-based design, synthesis, and biological evaluation of 2-aminopyrimidines, a novel series of receptor for advanced glycation end products (RAGE) inhibitors.

Using the approach of ligand-based drug design, we discovered a novel series of 4,6-disubstituted 2-aminopyrimidines as RAGE inhibitors. In transgenic mouse models of AD, one of the 4,6-bis(4-chlorophenyl)pyrimidine analogs, 59, significantly lowered the concentration of toxic soluble Aβ in the brain and improved cognitive function. SPR analysis confirmed the direct binding of 59 with RAGE, which should contribute to its biological activities via inhibition of the RAGE-Aβ interaction.

Human serum transthyretin levels correlate inversely with Alzheimer's disease.

Alzheimer's disease (AD) is the fastest growing neurodegenerative disease in the elderly population, and the search for therapeutic targets and diagnostic AD biomarkers is an exigent issue. Because amyloid-β (Aβ) aggregation constitutes the epicenter of AD pathology, Aβ-binding proteins that regulate Aβ aggregation, such as transthyretin (TTR), have attracted much attention. TTR binds to Aβ, prevents its aggregation, and consequently inhibits Aβ-induced cellular toxicity.

Identification of autoantibody against beta-amyloid peptide in the serum of elderly.

Alzheimer's disease (AD) is characterized by two major neurological features: amyloid deposits and neurofibrillary tangles in the brain. According to the amyloid cascade hypothesis, accumulation of amyloid-beta peptide (A-beta) plays a central role in the pathogenesis of AD. Several lines of evidence suggest that antibodies against A-beta play a protective role in the neuropathology of AD.

Effects of methamphetamine on single unit activity in rat medial prefrontal cortex in vivo.

To investigate how neuronal activity in the prefrontal cortex changes in an animal model of schizophrenia, we recorded single unit activity in the medial prefrontal cortex of urethane-anesthetized and awake rats following methamphetamine (MA) administration. Systemic MA injection (4 mg/kg, IP) induced inconsistent changes, that is, both enhancement and reduction, in unit discharge rate, with a subset of neurons transiently (<30 min) elevating their activities. The direction of firing rate change was poorly predicted by the mean firing rate or the degree of burst firing during the baseline period.

Reduced serum level of antibodies against amyloid beta peptide is associated with aging in Tg2576 mice.

Both active and passive immunization to eliminate amyloid plaques from the brain of patients with Alzheimer's disease (AD) have confirmed that amyloid beta (Abeta) vaccination does not only result in clearance of Abeta plaques but improves behavioral-cognitive deficits in animal models of AD. In the present study, the levels of naturally occurring serum antibodies against Abeta were measured in Tg2576 mice at various ages using ELISA to determine the relationship between aging and the level of anti-Abeta autoantibody. The level of anti-Abeta antibody fell significantly at the age of 9 months, at the age when amyloid plaques started to appear in the brain of Tg2576 mice, and was persistently low thereafter.

Branched diacylglycerol-lactones as potent protein kinase C ligands and alpha-secretase activators.

Using as our lead structure a potent PKC ligand (1) that we had previously described, we investigated a series of branched DAG-lactones to optimize the scaffold for PKC binding affinity and reduced lipophilicity, and we examined the potential utility of select compounds as alpha-secretase activators. Activation of alpha-secretase upon PKC stimulation by ligands causes increased degradation of the amyloid precursor protein (APP), resulting in enhanced secretion of sAPPalpha and reduced deposition of beta-amyloid peptide (Abeta), which is implicated in the pathogenesis of Alzheimer's disease. We modified in a systematic manner the C5-acyl group, the 3-alkylidene, and the lactone ring in 1 and established structure-activity relationships for this series of potent PKC ligands.

Transgenic potato expressing Abeta reduce Abeta burden in Alzheimer's disease mouse model.

Beta amyloid (Abeta) is believed one of the major pathogens of Alzheimer's disease (AD), and the reduction of Abeta is considered a primary therapeutic target. Immunization with Abeta can reduce Abeta burden and pathological features in transgenic AD model mice. Transgenic potato plants were made using genes encoding 5 tandem repeats of Abeta1-42 peptides with an ER retention signal.