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1.
Int J Mol Sci ; 24(2)2023 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-36674884

RESUMEN

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.


Asunto(s)
Neoplasias , Enfermedades Neurodegenerativas , Humanos , Receptores Purinérgicos P2X7 , Tomografía de Emisión de Positrones/métodos , Inflamación/diagnóstico por imagen , Inflamación/tratamiento farmacológico , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico
3.
J Med Chem ; 65(18): 12292-12318, 2022 09 22.
Artículo en Inglés | MEDLINE | ID: mdl-36084304

RESUMEN

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.


Asunto(s)
Enfermedad de Alzheimer , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Animales , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Colinesterasas , Donepezilo/uso terapéutico , Plomo/uso terapéutico , Ligandos , Pez Cebra/metabolismo
4.
J Med Chem ; 65(16): 11291-11308, 2022 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-35930402

RESUMEN

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.


Asunto(s)
Adenosina Trifosfato , Canales Iónicos , Adenosina Trifosfato/metabolismo , Sitios de Unión , Canales Iónicos/metabolismo , Dominios Proteicos , Receptores Purinérgicos P2X7/metabolismo , Relación Estructura-Actividad
5.
Molecules ; 27(7)2022 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-35408685

RESUMEN

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.


Asunto(s)
Hexanos , Receptor de Adenosina A3 , Animales , Células CHO , Cricetinae , Ligandos , Nucleósidos/química , Ensayo de Unión Radioligante , Receptor de Adenosina A3/química , Relación Estructura-Actividad
6.
Eur J Med Chem ; 226: 113838, 2021 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-34571173

RESUMEN

The P2X7 receptor (P2X7R) stands out among the purinergic receptors due to its strong involvement in the regulation of tumor growth and metastasis formation as well as in innate immune responses and afferent signal transmission. Numerous studies have pointed out the beneficial effects of P2X7R antagonism for the treatment of a variety of cancer types, inflammatory diseases, and chronic pain. Herein we describe the development of novel P2X7R antagonists, incorporating piperazine squaric diamides as a central element. Besides improving the antagonists' potency from pIC50 values of 5.7-7.6, ADME properties (logD7.4 value, plasma protein binding, in vitro metabolic stability) of the generated compounds were investigated and optimized to provide novel P2X7R antagonists with drug-like properties. Furthermore, docking studies revealed the antagonists binding to the allosteric binding pocket in two distinct binding poses, depending on the substitution of the central piperazine moiety.


Asunto(s)
Ciclobutanos/farmacología , Diamida/farmacología , Piperazina/farmacología , Antagonistas del Receptor Purinérgico P2X/farmacología , Receptores Purinérgicos P2X/metabolismo , Ciclobutanos/síntesis química , Ciclobutanos/química , Diamida/síntesis química , Diamida/química , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Estructura Molecular , Piperazina/síntesis química , Piperazina/química , Antagonistas del Receptor Purinérgico P2X/síntesis química , Antagonistas del Receptor Purinérgico P2X/química , Relación Estructura-Actividad , Células Tumorales Cultivadas
7.
Headache ; 51(5): 734-43, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21434910

RESUMEN

BACKGROUND: Neck muscle nociception mediated by nitric oxide may play a role in the pathophysiology of tension-type headache. OBJECTIVE: The present study addresses the involvement of neuronal nitric oxide synthase (nNOS) in the facilitation of neck muscle nociception after local application of nerve growth factor (NGF). METHODS: After administration of NGF into semispinal neck muscles, the impact of neck muscle noxious input on brainstem processing was monitored by the jaw-opening reflex in anesthetized mice. The modulatory effect of preceding and subsequent administration of an inhibitor of neuronal nitric oxide synthase on central facilitation was addressed in a controlled study. RESULTS: With preceding i.p. application of saline or 0.096 mg/kg of the specific nNOS inhibitor Nω-propyl-L-arginine (NPLA), NGF induced a sustained reflex facilitation within 60 minutes. Preceding injection of 0.96 mg/kg or 1.92 mg/kg NPLA completely prevented the potentially facilitatory effect of NGF. Subsequent administration of 0.96 mg/kg NPLA did not affect established NGF-evoked reflex facilitation. Thus, NPLA prevents facilitation of brainstem processing by noxious myofascial input from neck muscles in a dose-dependent manner. CONCLUSION: These findings suggest that nNOS is involved in the induction but not the maintenance of NGF-evoked facilitation of nociception in the brainstem. These results from an experimental animal model may support the idea of NOS and nNOS as potential targets for pharmacological treatment of tension-type headache.


Asunto(s)
Músculos del Cuello/inervación , Óxido Nítrico Sintasa de Tipo I/metabolismo , Dolor/enzimología , Cefalea de Tipo Tensional/enzimología , Animales , Arginina/análogos & derivados , Arginina/farmacología , Tronco Encefálico/enzimología , Modelos Animales de Enfermedad , Estimulación Eléctrica , Inhibidores Enzimáticos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Músculos del Cuello/efectos de los fármacos , Músculos del Cuello/fisiopatología , Factor de Crecimiento Nervioso/toxicidad , Dolor/fisiopatología , Reflejo/efectos de los fármacos , Cefalea de Tipo Tensional/inducido químicamente , Cefalea de Tipo Tensional/fisiopatología
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