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1.
Pain ; 161(1): 177-184, 2020 01.
Article in English | MEDLINE | ID: mdl-31490328

ABSTRACT

Chemotherapy-induced neuropathic pain (CINP) in both sexes compromises many current chemotherapeutics and lacks an FDA-approved therapy. We recently identified the sphingosine-1-phosphate receptor subtype 1 (S1PR1) and A3 adenosine receptor subtype (A3AR) as novel targets for therapeutic intervention. Our work in male rodents using paclitaxel, oxaliplatin, and bortezomib showed robust inhibition of CINP with either S1PR1 antagonists or A3AR agonists. The S1PR1 functional antagonist FTY720 (Gilenya) is FDA-approved for treating multiple sclerosis, and selective A3AR agonists are in advanced clinical trials for cancer and inflammatory disorders, underscoring the need for their expedited trials in patients with CINP as chemotherapy adjuncts. Our findings reveal that S1PR1 antagonists and A3AR agonists mitigate paclitaxel and oxaliplatin CINP in female and male rodents, but failed to block or reverse bortezomib-induced neuropathic pain (BINP) in females. Although numerous mechanisms likely underlie these differences, we focused on receptor levels. We found that BINP in male rats, but not in female rats, was associated with increased expression of A3AR in the spinal cord dorsal horn, whereas S1PR1 levels were similar in both sexes. Thus, alternative mechanisms beyond receptor expression may account for sex differences in response to S1PR1 antagonists. Morphine and duloxetine, both clinical analgesics, reversed BINP in female mice, demonstrating that the lack of response is specific to S1PR1 and A3AR agents. Our findings suggest that A3AR- and S1PR1-based therapies are not viable approaches in preventing and treating BINP in females and should inform future clinical trials of these drugs as adjuncts to chemotherapy.


Subject(s)
Antineoplastic Agents/adverse effects , Bortezomib/adverse effects , Neuralgia/drug therapy , Receptor, Adenosine A3/metabolism , Sphingosine-1-Phosphate Receptors/metabolism , Spinal Cord Dorsal Horn/metabolism , Adenosine A3 Receptor Antagonists/administration & dosage , Adenosine A3 Receptor Antagonists/therapeutic use , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/therapeutic use , Animals , Duloxetine Hydrochloride/administration & dosage , Duloxetine Hydrochloride/therapeutic use , Female , Fingolimod Hydrochloride/administration & dosage , Fingolimod Hydrochloride/therapeutic use , Male , Morphine/administration & dosage , Morphine/therapeutic use , Neuralgia/chemically induced , Oxaliplatin/adverse effects , Paclitaxel/adverse effects , Rats , Sex Factors , Sphingosine 1 Phosphate Receptor Modulators/administration & dosage , Sphingosine 1 Phosphate Receptor Modulators/therapeutic use , Spinal Cord Dorsal Horn/drug effects
2.
Int J Mol Sci ; 20(18)2019 Sep 13.
Article in English | MEDLINE | ID: mdl-31540220

ABSTRACT

Diabetic nephropathy (DN) is the main cause of end-stage renal disease, which remains incurable. The progression of DN is associated with progressive and irreversible renal fibrosis and also high levels of adenosine. Our aim was to evaluate the effects of ADORA3 antagonism on renal injury in streptozotocin-induced diabetic rats. An ADORA3 antagonist that was administered in diabetic rats greatly inhibited the levels of inflammatory interleukins IL-1ß and IL-18, meanwhile when adenosine deaminase was administered, there was a non-selective attenuation of the inflammatory mediators IL-1ß, IL-18, IL-6, and induction of IL-10. The ADORA3 antagonist attenuated the high glucose-induced activation of caspase 1 in HK2 cells in vitro. Additionally, ADORA3 antagonisms blocked the increase in caspase 1 and the nuclear localization of NFκB in the renal tubular epithelium of diabetic rats, both events that are involved in regulating the production and activation of IL-1ß and IL-18. The effects of the A3 receptor antagonist resulted in the attenuation of kidney injury, as evidenced by decreased levels of the pro-fibrotic marker α-SMA at histological levels and the restoration of proteinuria in diabetic rats. We conclude that ADORA3 antagonism represents a potential therapeutic target that mechanistically works through the selective blockade of the NLRP3 inflammasome.


Subject(s)
Adenosine A3 Receptor Antagonists/administration & dosage , Caspase 1/metabolism , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/drug therapy , Diabetic Nephropathies/prevention & control , Adenosine A3 Receptor Antagonists/pharmacology , Adenosine Deaminase/adverse effects , Animals , Cell Line , Diabetes Mellitus, Experimental/enzymology , Diabetic Nephropathies/chemically induced , Disease Models, Animal , Gene Expression Regulation/drug effects , Humans , Injections, Intraperitoneal , Interleukin-18/metabolism , Interleukin-1beta/metabolism , Kidney Tubules/drug effects , Kidney Tubules/enzymology , Male , Rats , Streptozocin
3.
Arch Pharm Res ; 40(8): 952-961, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28756559

ABSTRACT

LJ-2698, a highly potent human A3 adenosine receptor antagonist with nucleoside structure, was designed to have a minimal species dependence. For further pre-clinical studies, analytical method for the detection of LJ-2698 in rat plasma was developed by liquid chromatography-tandem mass. Plasma samples were processed by protein precipitation method with acetonitrile, using losartan as the internal standard (IS). Chromatographic separation was carried out using a Kinetex C18 column (100 × 4.6 mm; 100 Å; 2.6 µ) with acetonitrile/water with 0.2% (v/v) formic acid (65:35, v/v) in the isocratic mode at a flow rate of 0.4 mL/min. Mass spectrometric detection in multiple reaction monitoring mode was performed with positive electrospray ionization. The mass transitions of LJ-2698 and IS were m/z 412.3 â†’ 294.1 and m/z 423.1 â†’ 207.2, respectively. The calibration curves were linear in the range 5.00-5000 ng/mL (r 2 ≥ 0.998). The lower limit of quantification was established as 5.00 ng/mL. Within- and between-run precisions were <7.01%, as relative standard deviation; and accuracies were in the range 3.37-3.64%, as relative error. The validated method was successfully applied to its pharmacokinetic evaluation after intravenous and oral administration in rats, and the dose-dependent pharmacokinetic behavior of LJ-2698 was elucidated for the first time.


Subject(s)
Adenosine A3 Receptor Antagonists/pharmacokinetics , Thionucleosides/pharmacokinetics , Adenosine A3 Receptor Antagonists/administration & dosage , Administration, Intravenous , Administration, Oral , Animals , Calibration , Chromatography, Liquid , Dose-Response Relationship, Drug , Limit of Detection , Male , Rats, Sprague-Dawley , Reproducibility of Results , Spectrometry, Mass, Electrospray Ionization , Tandem Mass Spectrometry , Thionucleosides/administration & dosage
4.
Am J Clin Dermatol ; 17(3): 191-200, 2016 Jun.
Article in English | MEDLINE | ID: mdl-26923915

ABSTRACT

Several classes of new oral therapy are in use or in development for the treatment of psoriasis. Despite the high efficacy of biologics, new oral therapies remain important as patients generally prefer this mode of administration and they offer an alternative risk-benefit profile. In this review, we discuss the novel modes of action of these drugs, including modulation of cellular pathways involving diverse targets such as Janus kinase, phosphodiesterase 4, sphingosine 1-phosphate, A3 adenosine receptor and rho-associated kinase 2. We review the available evidence around licensed drugs (apremilast) and drugs that are advanced (tofacitinib) or early (ponesimod, baricitinib, peficitinib, INCB039110, CF101, KD025) in the development pipeline. The key limitations of these oral therapies are their modest efficacy profile (apremilast, ponesimod) and the limitations of their safety profile (tofacitinib, ponesimod), while the evidence for the early pipeline drugs are at phase II level only. Potential niches of current unmet needs include apremilast for patients with concomitant psoriatic arthritis, as combination treatments with biologic therapies, and/or for patients in whom multiple biologic therapies have failed due to immunogenicity and secondary inefficacy. The present knowledge gap regarding these novel drugs includes the need for longer clinical trials or observational studies to evaluate safety, and randomised phase III trials for the early pipeline drugs. We conclude that further research and data are necessary to conclusively establish the role of these agents in the current psoriasis treatment paradigm.


Subject(s)
Arthritis, Psoriatic/drug therapy , Phosphodiesterase 4 Inhibitors/therapeutic use , Piperidines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Psoriasis/drug therapy , Pyrimidines/therapeutic use , Pyrroles/therapeutic use , Thalidomide/analogs & derivatives , Thiazoles/therapeutic use , Adamantane/administration & dosage , Adamantane/adverse effects , Adamantane/analogs & derivatives , Adamantane/therapeutic use , Adenosine/administration & dosage , Adenosine/adverse effects , Adenosine/analogs & derivatives , Adenosine/therapeutic use , Adenosine A3 Receptor Antagonists/administration & dosage , Adenosine A3 Receptor Antagonists/adverse effects , Adenosine A3 Receptor Antagonists/therapeutic use , Administration, Oral , Azetidines/administration & dosage , Azetidines/adverse effects , Azetidines/therapeutic use , Biological Factors/therapeutic use , Biological Therapy , Clinical Trials as Topic , Humans , Isonicotinic Acids/administration & dosage , Isonicotinic Acids/adverse effects , Isonicotinic Acids/therapeutic use , Janus Kinases/antagonists & inhibitors , Niacinamide/administration & dosage , Niacinamide/adverse effects , Niacinamide/analogs & derivatives , Niacinamide/therapeutic use , Phosphodiesterase 4 Inhibitors/administration & dosage , Phosphodiesterase 4 Inhibitors/adverse effects , Piperidines/administration & dosage , Piperidines/adverse effects , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Purines , Pyrazoles , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Pyrroles/administration & dosage , Pyrroles/adverse effects , Receptors, Lysosphingolipid/metabolism , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Sulfonamides/therapeutic use , Thalidomide/administration & dosage , Thalidomide/adverse effects , Thalidomide/therapeutic use , Thiazoles/administration & dosage , Thiazoles/adverse effects , rho-Associated Kinases/antagonists & inhibitors
5.
Bioorg Med Chem Lett ; 24(15): 3302-6, 2014 Aug 01.
Article in English | MEDLINE | ID: mdl-24969016

ABSTRACT

2-Arylethynyl-(N)-methanocarba adenosine 5'-methyluronamides containing rigid N(6)-(trans-2-phenylcyclopropyl) and 2-phenylethynyl groups were synthesized as agonists for probing structural features of the A3 adenosine receptor (AR). Radioligand binding confirmed A3AR selectivity and N(6)-1S,2R stereoselectivity for one diastereomeric pair. The environment of receptor-bound, conformationally constrained N(6) groups was explored by docking to an A3AR homology model, indicating specific hydrophobic interactions with the second extracellular loop able to modulate the affinity profile. 2-Pyridylethynyl derivative 18 was administered orally in mice to reduce chronic neuropathic pain in the chronic constriction injury model.


Subject(s)
Adenosine A3 Receptor Antagonists/pharmacology , Nucleosides/pharmacology , Receptor, Adenosine A3/metabolism , Adenosine A3 Receptor Antagonists/administration & dosage , Adenosine A3 Receptor Antagonists/chemistry , Animals , CHO Cells , Chronic Pain/drug therapy , Cricetulus , Crystallography, X-Ray , Disease Models, Animal , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Ligands , Mice , Models, Molecular , Molecular Structure , Nucleosides/administration & dosage , Nucleosides/chemistry , Structure-Activity Relationship
6.
Am J Pathol ; 183(5): 1488-1497, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24001475

ABSTRACT

Adenosine in the normal kidney significantly elevates in response to cellular damage. The renal A3 adenosine receptor (A3AR) is up-regulated under stress, but the therapeutic effects of A3AR antagonists on chronic kidney disease are not fully understood. The present study examined the effect of LJ-1888 [(2R,3R,4S)-2-[2-chloro-6-(3-iodobenzylamino)-9H-purine-9-yl]-tetrahydrothiophene-3,4-diol], a newly developed potent, selective, species-independent, and orally active A3AR antagonist, on unilateral ureteral obstruction (UUO)-induced renal fibrosis. Pretreatment with LJ-1888 inhibited UUO-induced fibronectin and collagen I up-regulation in a dose-dependent manner. Masson's trichrome staining confirmed that LJ-1888 treatment effectively reduced UUO-induced interstitial collagen accumulation. Furthermore, delayed administration of LJ-1888 showed an equivalent therapeutic effect on tubulointerstitial fibrosis to that of losartan. Small-interfering A3AR transfection effectively inhibited transforming growth factor-ß1 (TGF-ß1)-induced fibronectin and collagen I up-regulation in proximal tubular cells similar to LJ-1888, confirming that the renoprotective effect of LJ-1888 resulted from A3AR blockade. UUO- or TGF-ß1-induced c-Jun N-terminal kinase and extracellular signal-regulated kinase phosphorylation decreased significantly after LJ-1888 administration. A3AR blockade reduced UUO- or TGF-ß1-induced up-regulation of lysyl oxidase, which induces cross-linking of extracellular matrix, suggesting that LJ-1888 may also regulate extracellular matrix accumulation via post-translational regulation. In conclusion, the present data demonstrate that the A3AR antagonist, LJ-1888, blocked the development and attenuated the progression of renal fibrosis, and they suggest that LJ-1888 may become a new therapeutic modality for renal interstitial fibrosis.


Subject(s)
Adenosine A3 Receptor Antagonists/therapeutic use , Adenosine/therapeutic use , Kidney Diseases/drug therapy , Kidney Diseases/prevention & control , Kidney Tubules, Proximal/pathology , Receptor, Adenosine A3/metabolism , Thiophenes/therapeutic use , Ureteral Obstruction/complications , Adenosine/pharmacology , Adenosine A3 Receptor Antagonists/administration & dosage , Adenosine A3 Receptor Antagonists/pharmacology , Animals , Collagen Type I/genetics , Collagen Type I/metabolism , Epithelial-Mesenchymal Transition/drug effects , Extracellular Matrix/drug effects , Extracellular Matrix/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Fibronectins/genetics , Fibronectins/metabolism , Fibrosis , Gene Expression Regulation/drug effects , JNK Mitogen-Activated Protein Kinases/metabolism , Kidney Diseases/enzymology , Kidney Diseases/pathology , Kidney Tubules, Proximal/drug effects , Kidney Tubules, Proximal/enzymology , Kidney Tubules, Proximal/metabolism , Male , Mice , Mice, Inbred C57BL , Phosphorylation/drug effects , Protein-Lysine 6-Oxidase/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects , Smad Proteins/metabolism , Thiophenes/pharmacology , Transforming Growth Factor beta1/pharmacology , Ureteral Obstruction/enzymology , Ureteral Obstruction/pathology
7.
Eur J Pharmacol ; 699(1-3): 62-6, 2013 Jan 15.
Article in English | MEDLINE | ID: mdl-23219789

ABSTRACT

A novel adenosine A(3) receptor antagonist (SSR161421) was characterized by both receptor binding assays and pharmacological tests. Binding studies on cloned human adenosine receptors showed that SSR161421 has high affinity for adenosine hA(3) receptors (K(i)=0.37 nM) with at least 1000-fold selectivity compared to hA(1), hA(2A) and hA(2B) receptors. The receptor antagonist nature of SSR161421 was determined in a functional study on Chinese hamster ovarian cells (CHO) cells expressing human adenosine A(3) receptors. SSR161421 competitively antagonized the effect of 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methylcarboxamide (Cl-IB-MECA) on cAMP production with a pA2 value in a luciferase reporter gene construct. In mice, intravenously administered SSR161421 inhibited the N6-(4-aminobenzyl)-adenosine-5'-N-methyl-uronamide dihydrochloride (AB-MECA) induced increase in plasma histamine levels (ED(50)=2.0mg/kg) and the Cl-IB-MECA evoked plasma extravasation (ID(50)=2.9 mg/kg) and oedema formation (ID(50)=4.6 mg/kg) in mouse ear.


Subject(s)
Adenosine A3 Receptor Agonists/pharmacology , Adenosine A3 Receptor Antagonists/pharmacology , Adenosine/analogs & derivatives , Aminoquinolines/pharmacology , Benzamides/pharmacology , Edema/drug therapy , Adenosine/administration & dosage , Adenosine/pharmacology , Adenosine A3 Receptor Antagonists/administration & dosage , Aminoquinolines/administration & dosage , Animals , Benzamides/administration & dosage , CHO Cells , Cricetinae , Cricetulus , Cyclic AMP/metabolism , Disease Models, Animal , Drug Interactions , Edema/pathology , Histamine/blood , Humans , Inhibitory Concentration 50 , Male , Mice , Plasma/metabolism , Receptors, Purinergic P1/drug effects , Receptors, Purinergic P1/metabolism
8.
Eur J Pharmacol ; 699(1-3): 172-9, 2013 Jan 15.
Article in English | MEDLINE | ID: mdl-23219796

ABSTRACT

The effects of a novel adenosine A(3) receptor antagonist, SSR161421, were examined on both antigen per se and adenosine receptor agonist-increased airway responses in antigen-sensitized guinea pigs. Adenosine (10(-5)M) and AB-MECA [N6-(4-aminobenzyl)-adenosine-5'-N-methyl-uronamide dihydrochloride] (10(-7)M) increased the antigen response up to 61 ± 3.0% and 88 ± 5.2% of maximal contraction, respectively. The agonists of adenosine A(1) and A(2) adenosine receptors NECA [1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-b-d-ribofuranuronamide-5'-N-ethylcarboxamidoadenosine], R-PIA [N(6)-R-phenylisopropyladenosine], and CGS21680 (10(-7)M) were ineffective. In vivo intravenous adenosine (600 µg/kg) and AB-MECA (30 µg/kg) increased the threshold antigen dose-induced bronchoconstriction by 214 ± 13.0% and 220 ± 15.2%, respectively. SSR161421 in vitro (IC(50)=5.9 × 10(-7)M) inhibited the AB-MECA-enhanced antigen-induced airway smooth muscle contractions and also in vivo the bronchoconstriction following either intravenous (ED(50)=0.008 mg/kg) or oral (ED(50)=0.03 mg/kg) administration in sensitized guinea pigs. Antigen itself could evoke tracheal contraction in vitro and bronchoconstriction in vivo in antigen-sensitized guinea pigs. SSR161421 (3 × 10(-6)M) decreased the AUC of the antigen-induced contraction-time curve to 20.8 ± 5.4% from the 100% control level. SSR161421 effectively reversed the antigen-induced bronchoconstriction, plasma leak and cell recruitment with EC(50) values of 0.33 mg/kg p.o., 0.02 mg/kg i.p. and 3 mg/kg i.p., respectively.


Subject(s)
Adenosine A3 Receptor Antagonists/pharmacology , Aminoquinolines/pharmacology , Antigens/immunology , Benzamides/pharmacology , Bronchoconstriction/drug effects , Adenosine/administration & dosage , Adenosine/analogs & derivatives , Adenosine/pharmacology , Adenosine A3 Receptor Antagonists/administration & dosage , Administration, Oral , Aminoquinolines/administration & dosage , Animals , Benzamides/administration & dosage , Bronchoconstriction/immunology , Dose-Response Relationship, Drug , Guinea Pigs , Inhibitory Concentration 50 , Injections, Intraperitoneal , Injections, Intravenous , Male , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/metabolism , Trachea/drug effects , Trachea/immunology
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