Drug development efforts
that focused on single targets failed to provide effective treatment
for Alzheimer’s disease (AD). Therefore, we designed cholinesterase
inhibition (ChEI)-based multi-target-directed ligands (MTDLs) to simultaneously
target AD-related receptors. We built a library of 70 compounds, sequentially
screened for ChEI, and determined σ1R, σ2R, NMDAR-GluN2B binding affinities, and P2X7R antagonistic
activities. Nine fulfilled in silico drug-likeness
criteria and did not display toxicity in three cell lines. Seven displayed
cytoprotective activity in two stress-induced cellular models. Compared
to donepezil, six showed equal/better synaptic protection in a zebrafish
model of acute amyloidosis-induced synaptic degeneration. Two P2X7R
antagonists alleviated the activation state of microglia in
vivo. Permeability studies were performed, and four did not
inhibit CYP450 3A4, 2D6, and 2C9. Therefore, four ChEI-based lead
MTDLs are promising drug candidates for synaptic integrity protection
and could serve as disease-modifying AD treatment. Our study also
proposes zebrafish as a useful preclinical tool for drug discovery
and development.
The homotrimeric P2X7 receptor (P2X7R) is expressed by virtually all cells of the innate and adaptive immune system and plays a crucial role in various pathophysiological processes such as autoimmune and neurodegenerative diseases, inflammation, neuropathic pain and cancer. Consequently, the P2X7R is considered a promising target for therapy and diagnosis. As the development of tracers comes hand-in-hand with the development of potent and selective receptor ligands, there is a rising number of PET tracers available in preclinical and clinical studies. This review analyzes the development of P2X7R positron emission tomography (PET) tracers and their potential in various PET imaging applications.
The adenosine A3 receptor is a promising target for treating and diagnosing inflammation and cancer. In this paper, a series of bicyclo[3.1.0]hexane-based nucleosides was synthesized and evaluated for their P1 receptor affinities in radioligand binding studies. The study focused on modifications at 1-, 2-, and 6-positions of the purine ring and variations of the 5′-position at the bicyclo[3.1.0]hexane moiety, closing existing gaps in the structure–affinity relationships. The most potent derivative 30 displayed moderate A3AR affinity (Ki of 0.38 μM) and high A3R selectivity. A subset of compounds varied at 5′-position was further evaluated in functional P2Y1R assays, displaying no off-target activity.
The orthosteric ATP-binding site of the P2X receptors
is poorly
understood. Only a few compounds were well characterized for their
P2X receptor functional activity and subtype selectivity. This study
represents the first fully functional characterization of various
ATP derivatives combined with in silico studies to advance the understanding
of SARs at the orthosteric binding sites of P2X receptors leading
to the identification of 2-chloro-3-trifluoromethylbenzoyl ATP ester
as a novel pan-P2X receptor agonist and several subtype-selective
P2X receptor agonists. Furthermore, esterification of both hydroxyl
functions of ATP using 1-naphthoic acid has led to compound 26 acting as an antagonist at P2X1-4 and P2X2/3 receptors
and an agonist at P2X7 receptors. This particular ATP derivative will
allow interrogating the P2X7 receptor function while antagonizing
all other P2X receptor subtypes and therefore serve as a valuable
pharmacological tool in the future.
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