Emerging targets and new small molecule therapies in Parkinson’s disease treatment

Parkinson’s disease (PD) is a common chronic degenerative disease of the central nervous system. Due to a rapidly aging society worldwide, PD morbidity is on the rise; however, the treatment of PD with conventional drugs carries serious adverse reactions and cannot fix the root cause of PD, the degeneration of dopaminergic neurons, which limits conventional drug usage in clinical practice. In recent years, research on the pathogenesis of PD and its clinical manifestations has led to the discovery of an increasing number of novel targets in PD, including several small molecule targeted compounds. In this paper, we analyze and summarize the most recently published PD literature and review several recently discovered novel targets in PD and their small molecule targeted pharmacologically active agents based on their mechanisms of action and pharmacodynamic profiles.     

Monitoring the early aggregatory behaviour and size of Aβ1-42 in the absence & presence of metal ions using dynamic light scattering

Background and aimAβ₁₋₄₂ is an amyloidogenic peptide found within senile plaques extracted from those who died with a diagnosis of Alzheimer’s disease. The potent neurotoxicity of this peptide is related to its propensity to form aggregated conformations in vivo, a process that is influenced by the species and concentration of metal ions present within the local environment. This study examines the impact of different metals upon the early aggregatory behaviour and size of Aβ₁₋₄₂ under simulated physiological conditions.MethodsThe size and aggregatory behaviour of Aβ₁₋₄₂ in the presence and absence of metal ions was monitored during the initial 30 min of fibril formation in real-time using dynamic light scattering.ResultsIntensity scattering measurements showed a clear tendency towards aggregation with regards to Aβ₁₋₄₂ only solutions (10 μM). Both equimolar Al³⁺ & Cu²⁺ lowered and stabilised the dimensions of Aβ₁₋₄₂ aggregates; however, a diminutive but significant increase in size was still observed over a 30-min period. While excess Al³⁺ continued to supress the size of Aβ_1−42, a 10-fold increase in the concentration of Cu²⁺ accelerated peptide aggregation relative to that observed for equimolar metal but not compared to Aβ₁₋₄₂ alone.ConclusionThese results infer that Al³⁺ ions stabilise and aid in the maintenance of smaller, toxic intermediates while excess Cu²⁺ facilitates the formation of larger, more inert, amorphous species exceeding 1 μm in size. Furthermore, we propose that metal-induced toxicity of Aβ₁₋₄₂ is reflective of their ability to preserve smaller oligomeric species in vitro.     

Development of bivalent compounds as potential neuroprotectants for Alzheimer’s disease

In our efforts to further investigate the impact of the spacer and membrane anchor to the neuroprotective activities, a series of bivalent compounds that contain cholesterol and extended spacers were designed, synthesized and biologically characterized. Our results support previous studies that incorporation of a piperazine ring into the spacer significantly improved the protective potency of bivalent compounds in MC65 cell model. Spacer length beyond 21 atoms does not add further benefits with 21MO being the most potent one with an EC₅₀ of 81.86 ± 11.91 nM. Our results also demonstrated that bivalent compound 21MO suppressed the production of mitochondria reactive oxygen species. Furthermore, our results confirmed that both of the spacer and membrane anchor moiety are essential to metal binding. Collectively, the results provide further evidence and information to guide optimization of such bivalent compounds as potential neuroprotectants for Alzheimer’s disease.     

Discovery of ABT-957: 1-Benzyl-5-oxopyrrolidine-2-carboxamides as selective calpain inhibitors with enhanced metabolic stability

Aberrant activation of calpain has been observed in various pathophysiological disorders including neurodegenerative diseases such as Alzheimer’s Disease. Here we describe our efforts on ketoamide-based 1-benzyl-5-oxopyrrolidine-2-carboxamides as a novel series of highly selective calpain inhibitors mitigating the metabolic liability of carbonyl reduction. The most advanced compound from this new series, namely A-1212805 (ABT-957, Alicapistat) proceeded to clinical phase I studies.     

Design,synthesis, biological evaluation,and molecular modeling studies of chalcone-rivastigmine hybrids as cholinesterase inhibitors

A series of novel chalcone-rivastigmine hybrids were designed, synthesized, and tested in vitro for their ability to inhibit human acetylcholinesterase and butyrylcholinesterase. Most of the target compounds showed hBChE selective activity in the micro- and submicromolar ranges. The most potent compound 3 exhibited comparable IC₅₀ to the commercially available drug (rivastigmine). To better understand their structure activity relationships (SAR) and mechanisms of enzyme-inhibitor interactions, kinetic and molecular modeling studies including molecular docking and molecular dynamics (MD) simulations were carried out. Furthermore, compound 3 blocks the formation of reactive oxygen species (ROS) in SH-SY5Y cells and shows the required druggability and low cytotoxicity, suggesting this hybrid is a promising multifunctional drug candidate for Alzheimer’s disease (AD) treatment.     

On the probable composition of ‘Jamaican stone’ aphrodisiac

A dangerous aphrodisiac, commonly known as ‘Jamaican stone’, banned by the U.S. Food and Drug Administration, has been studied by vibrational spectroscopy in order to solve the controversy on its composition. The results of the ATR-FTIR analysis revealed the presence of the α-pyrone ring, which is characteristic of bufadienolides from toad venom and bulbs of squill (Drimia maritima (L.) Stearn). This conclusion was reached after a comparative study with the spectra for phytochemicals derived from gambir and cat’s claw, two Uncaria species also preconized as aphrodisiacs and deemed as possible constituents of the ‘stone’. Owing to their physiologic similarities to digoxin, bufadienolides have been shown to produce a toxic profile similar to that of digoxin, although the lack one of the side chains found on digoxin should allow the use of hemodialysis to treat ‘Jamaican stone’ overdose.     

Design,synthesis, and evaluation of a selective chemosensor for leucine-rich repeat kinase 2

We describe the design, synthesis, and evaluation of a selective activity probe for leucine-rich repeat kinase 2 (LRRK2), a possible molecular target for the treatment of Parkinson’s disease. Our optimal chemosensor design, termed Nictide-S2, incorporates a phosphorylation-sensitive sulfonamido-oxine fluorophore at an engineered cysteine within the substrate sequence. This design allows for the direct, real-time analysis of LRRK2 kinase activity with a detection limit of 2.5 nM. Under optimized conditions, we measured a Z′ factor of 0.7 demonstrating the potential utility of this assay for inhibitor screening. Off-target kinases capable of phosphorylating Nictide-S2 are identified and an optimized inhibitor cocktail for suppressing background signal is provided. The resulting chemosensor could be utilized to identify LRRK2 inhibitors as well as selectively report on LRRK2 activity in the presence of off-target kinases.