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1.
ACS Chem Neurosci ; 12(18): 3410-3417, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34469110

RESUMO

Adenosine receptor (AR) radiotracers for positron emission tomography (PET) have provided knowledge on the in vivo biodistribution of ARs in the central nervous system (CNS), which is of therapeutic interest for various neuropsychiatric disorders. Additionally, radioligands that can image changes in endogenous adenosine levels in different physiological and pathological conditions are still lacking. The binding of known antagonist adenosine A1 receptor (A1R) radiotracer, [11C]MDPX, failed to be inhibited by elevated endogenous adenosine in a rodent PET study. Since most of the known AR PET radiotracers were antagonists, we propose that an A1R agonist radioligand may possess higher sensitivity to measure changes in endogenous adenosine concentration. Herein, we report our latest findings toward the development of a full agonist adenosine A1 radioligand for PET. Based on a 3,5-dicyanopyridine template, 16 new derivatives were designed and synthesized to optimize both binding affinity and functional activity, resulting in two full agonists (compounds 27 and 29) with single-digit nanomolar affinities and good subtype selectivity (A1/A2A selectivity of ∼1000-fold for compound 27 and 29-fold for compound 29). Rapid O-[11C]methylation provided [11C]27 and [11C]29 in high radiochemical yields and radiochemical purity. However, subsequent brain PET imaging in rodents showed poor brain permeability for both radioligands. An in vivo PET study using knockout mice for MDR 1a/a, BCRP, and MRP1 indicated that these compounds might be substrates for brain efflux pumps. In addition, in silico evaluation using multiparameter optimization identified high molecular weight and high polar surface area as the main molecular descriptors responsible for low brain penetration. These results will provide further insight toward development of full agonist adenosine A1 radioligands and also highly potent CNS A1AR drugs.


Assuntos
Proteínas de Neoplasias , Agonistas do Receptor Purinérgico P1 , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Adenosina , Animais , Camundongos , Tomografia por Emissão de Pósitrons , Distribuição Tecidual
2.
J Med Chem ; 64(17): 12525-12536, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34435786

RESUMO

Distinguishing compounds' agonistic or antagonistic behavior would be of great utility for the rational discovery of selective modulators. We synthesized truncated nucleoside derivatives and discovered 6c (Ki = 2.40 nM) as a potent human A3 adenosine receptor (hA3AR) agonist, and subtle chemical modification induced a shift from antagonist to agonist. We elucidated this shift by developing new hA3AR homology models that consider the pharmacological profiles of the ligands. Taken together with molecular dynamics (MD) simulation and three-dimensional (3D) structural network analysis of the receptor-ligand complex, the results indicated that the hydrogen bonding with Thr943.36 and His2727.43 could make a stable interaction between the 3'-amino group with TM3 and TM7, and the corresponding induced-fit effects may play important roles in rendering the agonistic effect. Our results provide a more precise understanding of the compounds' actions at the atomic level and a rationale for the design of new drugs with specific pharmacological profiles.

3.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360719

RESUMO

Agonists of the Gi protein-coupled A3 adenosine receptor (A3AR) have shown important pain-relieving properties in preclinical settings of several pain models. Active as a monotherapy against chronic pain, A3AR agonists can also be used in combination with classic opioid analgesics. Their safe pharmacological profile, as shown by clinical trials for other pathologies, i.e., rheumatoid arthritis, psoriasis and fatty liver diseases, confers a realistic translational potential, thus encouraging research studies on the molecular mechanisms underpinning their antinociceptive actions. A number of pathways, involving central and peripheral mechanisms, have been proposed. Recent evidence showed that the prototypical A3AR agonist Cl-IB-MECA and the new, highly selective, A3AR agonist MRS5980 inhibit neuronal (N-type) voltage-dependent Ca2+ currents in dorsal root ganglia, a known pain-related mechanism. Other proposed pathways involve reduced cytokine production, immune cell-mediated responses, as well as reduced microglia and astrocyte activation in the spinal cord. The aim of this review is to summarize up-to-date information on A3AR in the context of pain, including cellular and molecular mechanisms underlying this effect. Based on their safety profile shown in clinical trials for other pathologies, A3AR agonists are proposed as novel, promising non-narcotic agents for pain control.


Assuntos
Agonistas do Receptor A3 de Adenosina/uso terapêutico , Sinalização do Cálcio/efeitos dos fármacos , Gânglios Espinais , Dor , Receptor A3 de Adenosina/metabolismo , Animais , Astrócitos/metabolismo , Gânglios Espinais/metabolismo , Gânglios Espinais/fisiopatologia , Humanos , Microglia/metabolismo , Dor/tratamento farmacológico , Dor/metabolismo , Dor/fisiopatologia
4.
Biochem Pharmacol ; 192: 114739, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34418353

RESUMO

Hepatic insulin resistance (IR) and enhanced hepatic glucose production (HGP) are key features of type 2 diabetes (T2D), contributing to fasting hyperglycemia. Adenosine receptors (ARs) are G protein-coupled and expressed in hepatocytes. Here, we explored the role of hepatic Gi/o-coupled A1AR on insulin resistance and glucose fluxes associated with obesity. We generated a mouse model with hepatocyte-specific deletion of A1AR (A1LΔ/Δ), which was compared with whole body knockout of A1AR or A1AR/A3AR (both Gi-coupled). Selective deletion of hepatic A1AR resulted in a modest improvement in insulin sensitivity. In addition, HFD A1LΔ/Δ mice showed decreased fasting glucose levels. Hyperinsulinemic-euglycemic clamp studies demonstrated enhanced insulin sensitivity with no change in HGP in HFD A1LΔ/Δ mice. Similar to A1LΔ/Δ, fasting blood glucose levels were significantly reduced in whole body A1Δ/Δ and A1Δ/ΔA3Δ/Δ compared to wild-type mice. Taken together, our data support the concept that blocking hepatic A1AR may decrease fasting blood glucose levels without directly affecting hepatocyte glucose metabolism and insulin sensitivity.

5.
Front Endocrinol (Lausanne) ; 12: 718429, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34456873

RESUMO

Extracellular nucleosides and nucleotides activate a group of G protein-coupled receptors (GPCRs) known as purinergic receptors, comprising adenosine and P2Y receptors. Furthermore, purinergic P2X ion channels are activated by ATP. These receptors are expressed in liver resident cells and play a critical role in maintaining liver function. In the normal physiology, these receptors regulate hepatic metabolic processes such as insulin responsiveness, glycogen and lipid metabolism, and bile secretion. In disease states, ATP and other nucleotides serve as danger signals and modulate purinergic responses in the cells. Recent studies have demonstrated that purinergic receptors play a significant role in the development of metabolic syndrome associated non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, hepatocellular carcinoma (HCC) and liver inflammation. In this concise review, we dissect the role of purinergic signaling in different liver resident cells involved in maintaining healthy liver function and in the development of the above-mentioned liver pathologies. Moreover, we discuss potential therapeutic strategies for liver diseases by targeting adenosine, P2Y and P2X receptors.

6.
Eur J Med Chem ; 223: 113607, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34171656

RESUMO

A series of adenosine and 2'-deoxyadenosine pairs modified with a 1,12-dicarba-closo-dodecaborane cluster or alternatively with a phenyl group at the same position was synthesized, and their affinity was determined at A1, A2A, A2B and A3 adenosine receptors (ARs). While AR affinity differences were noted, a general tendency to preferentially bind A3 AR over other ARs was observed for most tested ligands. In particular, 5'-ethylcarbamoyl-N6-(3-phenylpropyl)adenosine (18), N6-(3-phenylpropyl)-2-chloroadenosine (24) and N6-(3-phenylpropyl)adenosine (40) showed nanomolar A3 affinity (Ki 4.5, 6.4 and 7.5 nM, respectively). Among the boron cluster-containing compounds, the highest A3 affinity (Ki 206 nM) was for adenosine derivative 41 modified at C2. In the matched molecular pairs, analogs bearing boron clusters were found to show lower binding affinity for adenosine receptors than the corresponding phenyl analogs. Nevertheless, interestingly, several boron cluster modified adenosine ligands showed significantly higher A3 receptor selectivity than the corresponding phenyl analogs: 7vs. 8, 15vs. 16, 17vs. 18.


Assuntos
Agonistas do Receptor A3 de Adenosina/farmacologia , Adenosina/análogos & derivados , Adenosina/farmacologia , Receptor A3 de Adenosina/metabolismo , Adenosina/metabolismo , Agonistas do Receptor A3 de Adenosina/síntese química , Agonistas do Receptor A3 de Adenosina/metabolismo , Animais , Compostos de Boro/síntese química , Compostos de Boro/metabolismo , Compostos de Boro/farmacologia , Células CHO , Cricetulus , Células HEK293 , Humanos , Ligantes , Estrutura Molecular , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Relação Estrutura-Atividade
7.
Pharmacol Res ; 170: 105731, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34157422

RESUMO

Psoriasis is a chronic and relapsing inflammatory skin disease lacking a cure that affects approximately 2% of the population. Defective keratinocyte proliferation and differentiation, and aberrant immune responses are major factors in its pathogenesis. Available treatments for moderate to severe psoriasis are directed to immune system causing systemic immunosuppression over time, and thus concomitant serious side effects (i.e. infections and cancer) may appear. In recent years, the Gi protein-coupled A3 receptor (A3R) for adenosine has been suggested as a novel and very promising therapeutic target for psoriasis. Accordingly, selective, and high affinity A3R agonists are known to induce robust anti-inflammatory effects in animal models of autoimmune inflammatory diseases. Here, we demonstrated the efficacy of a selective A3R agonist, namely MRS5698, in preventing the psoriatic-like phenotype in the IL-23 mouse model of psoriasis. Subsequently, we photocaged this molecule with a coumarin moiety to yield the first photosensitive A3R agonist, MRS7344, which in photopharmacological experiments prevented the psoriatic-like phenotype in the IL-23 animal model. Thus, we have demonstrated the feasibility of using a non-invasive, site-specific, light-directed approach to psoriasis treatment.

8.
J Neurosci Res ; 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34075613

RESUMO

Opioids are potent analgesics, but their pain-relieving effects diminish with repeated use. The reduction in analgesic potency is a hallmark of opioid analgesic tolerance, which hampers opioid pain therapy. In the central nervous system, opioid analgesia is critically modulated by adenosine, a purine nucleoside implicated in the beneficial and detrimental actions of opioid medications. Here, we focus on the A3 adenosine receptor (A3 AR) in opioid analgesic tolerance. Intrathecal administration of the A3 AR agonist MRS5698 with daily systemic morphine in male rats attenuated the reduction in morphine antinociception over 7 days. In rats with established morphine tolerance, intrathecal MRS5698 partially restored the antinociceptive effects of morphine. However, when MRS5698 was discontinued, these animals displayed a reduced antinociceptive response to morphine. Our results suggest that MRS5698 acutely and transiently potentiates morphine antinociception in tolerant rats. By contrast, in morphine-naïve rats MRS5698 treatment did not impact thermal nociceptive threshold or affect antinociceptive response to a single injection of morphine. Furthermore, we found that morphine-induced adenosine release in cerebrospinal fluid was blunted in tolerant animals, but total spinal A3 AR expression was not affected. Collectively, our findings indicate that spinal A3 AR activation acutely potentiates morphine antinociception in the opioid tolerant state.

9.
JCI Insight ; 6(10)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34027896

RESUMO

Obesity is the major driver of the worldwide epidemic in type 2 diabetes (T2D). In the obese state, chronically elevated plasma free fatty acid levels contribute to peripheral insulin resistance, which can ultimately lead to the development of T2D. For this reason, drugs that are able to regulate lipolytic processes in adipocytes are predicted to have considerable therapeutic potential. Gi-coupled P2Y14 receptor (P2Y14R; endogenous agonist, UDP-glucose) is abundantly expressed in both mouse and human adipocytes. Because activated Gi-type G proteins exert an antilipolytic effect, we explored the potential physiological relevance of adipocyte P2Y14Rs in regulating lipid and glucose homeostasis. Metabolic studies indicate that the lack of adipocyte P2Y14R enhanced lipolysis only in the fasting state, decreased body weight, and improved glucose tolerance and insulin sensitivity. Mechanistic studies suggested that adipocyte P2Y14R inhibits lipolysis by reducing lipolytic enzyme activity, including ATGL and HSL. In agreement with these findings, agonist treatment of control mice with a P2Y14R agonist decreased lipolysis, an effect that was sensitive to inhibition by a P2Y14R antagonist. In conclusion, we demonstrate that adipose P2Y14Rs were critical regulators of whole-body glucose and lipid homeostasis, suggesting that P2Y14R antagonists might be beneficial for the therapy of obesity and T2D.

10.
Bioorg Med Chem Lett ; 45: 128137, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34048882

RESUMO

The Gq-coupled P2Y6 receptor (P2Y6R) is a component of the purinergic signaling system and functions in inflammatory, cardiovascular and metabolic processes. UDP, the native P2Y6R agonist and P2Y14R partial agonist, is subject to hydrolysis by ectonucleotidases. Therefore, we have synthesized UDP/CDP analogues containing a stabilizing α,ß-methylene bridge as P2Y6R agonists and identified compatible affinity-enhancing pyrimidine modifications. A distal binding region on the receptor was explored with 4-benzyloxyimino cytidine 5'-diphosphate analogues and their potency determined in a calcium mobilization assay. A 4-trifluoromethyl-benzyloxyimino substituent in 25 provided the highest human P2Y6R potency (MRS4554, 0.57 µM), and a 5-fluoro substitution of the cytosine ring in 28 similarly enhanced potency, with >175- and 39-fold selectivity over human P2Y14R, respectively. However, 3-alkyl (31-33, 37, 38), ß-d-arabinofuranose (39) and 6-aza (40) substitution prevented P2Y6R activation. Thus, we have identified new α,ß-methylene bridged N4-extended CDP analogues as P2Y6R agonists that are highly selective over the P2Y14R.

11.
Bioorg Med Chem Lett ; 41: 128008, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33831560

RESUMO

Various 6-alkynyl analogues of a known 3-nitro-2-(trifluoromethyl)-2H-chromene antagonist 3 of the Gq-coupled P2Y6 receptor (P2Y6R) were synthesized using a Sonogashira reaction to replace a 6-iodo group. The analogues were tested in a functional assay consisting of inhibition of calcium mobilization in P2Y6R-expressing astrocytoma cells elicited by native P2Y6R agonist UDP. 6-Ethynyl and 6-cyano groups were installed, and the alkynes were extended through both alkyl and aryl spacers. The most potent antagonists, with IC50 of ~1 µM, were found to be trialkylsilyl-ethynyl 7 and 8 (3-5 fold greater affinity than reference 3), t-butyl prop-2-yn-1-ylcarbamate 14 and p-carboxyphenyl-ethynyl 16 derivatives, and 3 and 8 displayed surmountable antagonism of UDP-induced production of inositol phosphates. Other chain-extended terminal carboxylate derivatives were less potent than the corresponding methyl ester derivatives. Thus, the 6 position in this chromene series is suitable for derivatization with flexibility of substitution, even with sterically extended chains, without losing P2Y6R affinity. However, a 3-carboxylic acid or 3-ester substitution did not serve as a nitro bioisostere, as the affinity was eliminated. These compounds provide additional ligand tools for the underexplored P2Y6R, which is a target for inflammatory, neurodegenerative and metabolic diseases.


Assuntos
Benzopiranos/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2/metabolismo , Benzopiranos/síntese química , Benzopiranos/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Antagonistas do Receptor Purinérgico P2Y/síntese química , Antagonistas do Receptor Purinérgico P2Y/química , Relação Estrutura-Atividade
12.
J Clin Invest ; 131(7)2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33792561

RESUMO

Airway eosinophilia is a hallmark of allergic asthma and is associated with mucus production, airway hyperresponsiveness, and shortness of breath. Although glucocorticoids are widely used to treat asthma, their prolonged use is associated with several side effects. Furthermore, many individuals with eosinophilic asthma are resistant to glucocorticoid treatment, and they have an unmet need for novel therapies. Here, we show that UDP-glucose (UDP-G), a nucleotide sugar, is selectively released into the airways of allergen-sensitized mice upon their subsequent challenge with that same allergen. Mice lacking P2Y14R, the receptor for UDP-G, had decreased airway eosinophilia and airway hyperresponsiveness compared with wild-type mice in a protease-mediated model of asthma. P2Y14R was dispensable for allergic sensitization and for the production of type 2 cytokines in the lung after challenge. However, UDP-G increased chemokinesis in eosinophils and enhanced their response to the eosinophil chemoattractant, CCL24. In turn, eosinophils triggered the release of UDP-G into the airway, thereby amplifying eosinophilic recruitment. This positive feedback loop was sensitive to therapeutic intervention, as a small molecule antagonist of P2Y14R inhibited airway eosinophilia. These findings thus reveal a pathway that can be therapeutically targeted to treat asthma exacerbations and glucocorticoid-resistant forms of this disease.


Assuntos
Asma/imunologia , Eosinófilos/imunologia , Eosinofilia Pulmonar/imunologia , Receptores Purinérgicos P2Y/imunologia , Uridina Difosfato Glucose/imunologia , Alérgenos/imunologia , Animais , Asma/genética , Asma/patologia , Quimiocina CCL24/genética , Quimiocina CCL24/imunologia , Eosinófilos/patologia , Masculino , Camundongos , Camundongos Knockout , Eosinofilia Pulmonar/genética , Eosinofilia Pulmonar/patologia , Receptores Purinérgicos P2Y/deficiência , Células Th2/imunologia , Células Th2/patologia , Uridina Difosfato Glucose/genética
13.
Int J Mol Sci ; 22(7)2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33801676

RESUMO

Atrial fibrillation (AF) is the most common form of cardiac arrhythmia seen in clinical practice. While some clinical parameters may predict the transition from paroxysmal to persistent AF, the molecular mechanisms behind the AF perpetuation are poorly understood. Thus, oxidative stress, calcium overload and inflammation, among others, are believed to be involved in AF-induced atrial remodelling. Interestingly, adenosine and its receptors have also been related to AF development and perpetuation. Here, we investigated the expression of adenosine A2A receptor (A2AR) both in right atrium biopsies and peripheral blood mononuclear cells (PBMCs) from non-dilated sinus rhythm (ndSR), dilated sinus rhythm (dSR) and AF patients. In addition, plasma adenosine content and adenosine deaminase (ADA) activity in these subjects were also determined. Our results revealed increased A2AR expression in the right atrium from AF patients, as previously described. Interestingly, increased levels of adenosine content and reduced ADA activity in plasma from AF patients were detected. An increase was observed when A2AR expression was assessed in PBMCs from AF subjects. Importantly, a positive correlation (P=0.001) between A2AR expression in the right atrium and PBMCs was observed. Overall, these results highlight the importance of the A2AR in AF and suggest that the evaluation of this receptor in PBMCs may be potentially be useful in monitoring disease severity and the efficacy of pharmacological treatments in AF patients.


Assuntos
Fibrilação Atrial/sangue , Leucócitos Mononucleares/citologia , Receptor A2A de Adenosina/sangue , Regulação para Cima , Adenosina/metabolismo , Adenosina Desaminase/metabolismo , Idoso , Idoso de 80 Anos ou mais , Remodelamento Atrial , Feminino , Células HEK293 , Átrios do Coração , Humanos , Masculino , Microscopia Confocal , Pessoa de Meia-Idade
14.
J Med Chem ; 64(8): 5099-5122, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33787273

RESUMO

A known zwitterionic, heterocyclic P2Y14R antagonist 3a was substituted with diverse groups on the central phenyl and terminal piperidine moieties, following a computational selection process. The most potent analogues contained an uncharged piperidine bioisostere, prescreened in silico, while an aza-scan (central phenyl ring) reduced P2Y14R affinity. Piperidine amide 11, 3-aminopropynyl 19, and 5-(hydroxymethyl)isoxazol-3-yl) 29 congeners in the triazole series maintained moderate receptor affinity. Adaption of 5-(hydroxymethyl)isoxazol-3-yl gave the most potent naphthalene-containing (32; MRS4654; IC50, 15 nM) and less active phenylamide-containing (33) scaffolds. Thus, a zwitterion was nonessential for receptor binding, and molecular docking and dynamics probed the hydroxymethylisoxazole interaction with extracellular loops. Also, amidomethyl ester prodrugs were explored to reversibly block the conserved carboxylate group to provide neutral analogues, which were cleavable by liver esterase, and in vivo efficacy demonstrated. We have, in stages, converted zwitterionic antagonists into neutral molecules designed to produce potent P2Y14R antagonists for in vivo application.


Assuntos
Piperidinas/química , Antagonistas do Receptor Purinérgico P2/química , Receptores Purinérgicos P2/metabolismo , Animais , Sítios de Ligação , Modelos Animais de Doenças , Desenho de Fármacos , Humanos , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neuralgia/tratamento farmacológico , Piperidinas/metabolismo , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Antagonistas do Receptor Purinérgico P2/metabolismo , Antagonistas do Receptor Purinérgico P2/uso terapêutico , Receptores Purinérgicos P2/química , Receptores Purinérgicos P2/genética , Solubilidade , Relação Estrutura-Atividade , Triazóis/química
15.
J Clin Invest ; 131(7)2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33621215

RESUMO

The A3 adenosine receptor (A3AR) has emerged as a therapeutic target with A3AR agonists to tackle the global challenge of neuropathic pain, and investigation into its mode of action is essential for ongoing clinical development. Immune cell A3ARs, and their activation during pathology, modulate cytokine release. Thus, the use of immune cells as a cellular substrate for the pharmacological action of A3AR agonists is enticing, but unknown. The present study discovered that Rag-KO mice lacking T and B cells, as compared with WT mice, are insensitive to the anti-allodynic effects of A3AR agonists. Similar findings were observed in interleukin-10 and interleukin-10 receptor knockout mice. Adoptive transfer of CD4+ T cells from WT mice infiltrated the dorsal root ganglion (DRG) and restored A3AR agonist-mediated anti-allodynia in Rag-KO mice. CD4+ T cells from Adora3-KO or Il10-KO mice did not. Transfer of CD4+ T cells from WT mice, but not Il10-KO mice, into Il10-KO mice or Adora3-KO mice fully reinstated the anti-allodynic effects of A3AR activation. Notably, A3AR agonism reduced DRG neuron excitability when cocultured with CD4+ T cells in an IL-10-dependent manner. A3AR action on CD4+ T cells infiltrated in the DRG decreased phosphorylation of GluN2B-containing N-methyl-D-aspartate receptors at Tyr1472, a modification associated with regulating neuronal hypersensitivity. Our findings establish that activation of A3AR on CD4+ T cells to release IL-10 is required and sufficient evidence for the use of A3AR agonists as therapeutics.


Assuntos
Agonistas do Receptor A3 de Adenosina/farmacologia , Linfócitos T CD4-Positivos/imunologia , Gânglios Espinais/imunologia , Interleucina-10/imunologia , Neuralgia/tratamento farmacológico , Neurônios/imunologia , Receptor A3 de Adenosina/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos T CD4-Positivos/patologia , Gânglios Espinais/patologia , Interleucina-10/genética , Camundongos , Camundongos Knockout , Neuralgia/genética , Neuralgia/imunologia , Neuralgia/patologia , Neurônios/patologia , Receptor A3 de Adenosina/genética
17.
Eur J Med Chem ; 212: 113125, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33422981

RESUMO

Thiouracil and thiocytosine are important heterocyclic pharmacophores having pharmacological diversity. Antitumor and antiviral activity is commonly associated with thiouracil and thiocytosine derivatives, which are well known fragments for adenosine receptor affinity with many associated pharmacological properties. In this respect, 33 novel compounds have been synthesized in two groups: 24 thiouracil derivatives (4a-x) and 9 thiocytosine derivatives (5a-i). Antitumor activity of all the compounds was determined in the U87 MG glioblastoma cell line. Compound 5e showed an anti-proliferative IC50 of 1.56 µM, which is slightly higher activity than cisplatin (1.67 µM). The 11 most active compounds showed no signficant binding to adenosine A1, A2A or A2B receptors at 1 µM. Brain tumors express high amounts of phosphodiesterases. Compounds were tested for PDE4 inhibition, and 5e and 5f showed the best potency (5e: 3.42 µM; 5f: 0.97 µM). Remakably, those compounds were also the most active against U87MG. However, the compounds lacked a cytotoxic effect on the HEK293 healthy cell line, which encourages further investigation.


Assuntos
Antineoplásicos/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Citosina/farmacologia , Glioblastoma/tratamento farmacológico , Inibidores da Fosfodiesterase 4/farmacologia , Receptores Purinérgicos P1/metabolismo , Tiouracila/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citosina/análogos & derivados , Citosina/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Estrutura Molecular , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Relação Estrutura-Atividade , Tiouracila/síntese química , Tiouracila/química
18.
Purinergic Signal ; 17(1): 3-8, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32794053

RESUMO

Geoffrey Burnstock made a chance observation early in his research career that did not fit the conventional scientific dogma-non-noradrenergic, non-cholinergic (NANC) nerves. Instead of rejecting these as an artifact, he followed their logical course to characterize the actions of extracellular ATP on nerves and muscles, eventually founding a large branch of pharmacology around purinergic signaling. The solid proof that validated his concept and dismissed many detractors was the cloning of seven ionotropic P2X receptors and eight metabotropic P2Y receptors, which are expressed in some combination in every tissue and organ. Given the broad importance of this signaling system in biology, medicinal chemists, inspired by Burnstock, began creating synthetic agonists and antagonists for these purinergic receptors. Various ligands have advanced to clinical trials, for disorders of the immune, nervous, cardiovascular, and other systems, and a few are already approved. Thus, medically important approaches have been derived from Burnstock's original pharmacological concepts and his constant guiding of the course of the field. The therapeutic potential of modulators of purinergic signaling is vast.

19.
Biochem Pharmacol ; 187: 114300, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33203518

RESUMO

Geoffrey Burnstock, the founder of the field of purinergic signaling research passed away in Melbourne, Australia on June 3rd, 2020, at the age of 91. With his death, the world of biomedical research lost one of its most passionate, creative and unconventional thought leaders. He was an inspiration to the many researchers he interacted with for more than 50 years and a frequent irritation to those in the administrative establishment. Geoff never considered himself a pharmacologist having being trained as a zoologist and becoming an autonomic neurophysiologist based on his evolving interests in systems and disease-related research. By the end of his life he had: published some 1550 papers; been cited more than 125,000 times; had an h-index of 156 and had supervised over 100 Ph.D. students. His indelible legacy, based on a holistic, data-based, multidisciplinary, unconventional "outside the box" approach to research was reflected in two of the seminal findings in late 20th century biomedical research: the purinergic neurotransmitter hypothesis and the concept of co-neurotransmission, both of which were initially received by his peers with considerable skepticism that at times verged on disdain. Nonetheless, while raising hackles and threatening the status quo, Geoff persevered and prevailed, becoming a mentor for several generations of biomedical researchers. In this review we provide a joint perspective on Geoff Burnstock's legacy in research.

20.
Br J Pharmacol ; 178(3): 489-514, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33125712

RESUMO

The known seven mammalian receptor subunits (P2X1-7) form cationic channels gated by ATP. Three subunits compose a receptor channel. Each subunit is a polypeptide consisting of two transmembrane regions (TM1 and TM2), intracellular N- and C-termini, and a bulky extracellular loop. Crystallization allowed the identification of the 3D structure and gating cycle of P2X receptors. The agonist-binding pocket is located at the intersection of two neighbouring subunits. In addition to the mammalian P2X receptors, their primitive ligand-gated counterparts with little structural similarity have also been cloned. Selective agonists for P2X receptor subtypes are not available, but medicinal chemistry supplied a range of subtype-selective antagonists, as well as positive and negative allosteric modulators. Knockout mice and selective antagonists helped to identify pathological functions due to defective P2X receptors, such as male infertility (P2X1), hearing loss (P2X2), pain/cough (P2X3), neuropathic pain (P2X4), inflammatory bone loss (P2X5), and faulty immune reactions (P2X7).


Assuntos
Trifosfato de Adenosina , Animais , Ligantes , Masculino , Camundongos , Camundongos Knockout , Receptores Purinérgicos P2X2
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