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Adenosine Receptor Agonist

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Kenneth A Jacobson – 1st expert on this subject based on the ideXlab platform

  • Design and in vivo activity of A_3 Adenosine Receptor Agonist prodrugs
    Purinergic Signalling, 2020
    Co-Authors: R. Rama Suresh, Dilip K Tosh, Shanu Jain, Zhoumou Chen, Yanling Ma, Maren C. Podszun, Yaron Rotman, Daniela Salvemini, Kenneth A Jacobson

    Abstract:

    Prodrugs (MRS7422, MRS7476) of highly selective A_3 Adenosine Receptor (AR) Agonists Cl-IB-MECA and MRS5698, respectively, were synthesized by succinylation of the 2′ and 3′ hydroxyl groups, and the parent, active drug was shown to be readily liberated upon incubation with liver esterases. The prodrug MRS7476 had greatly increased aqueous solubility compared with parent MRS5698 and was fully efficacious and with a longer duration than MRS7422 in reversing mouse neuropathic pain (chronic constriction injury model, 3 μmol/kg, p.o.), a known A_3AR effect. MRS7476 (5 mg/kg, p.o., twice daily) was found to protect against non-alcoholic steatohepatitis (NASH) in the STAM mouse model, indicated by the NAFLD activity score. Hepatocyte ballooning, IL-10 production, and liver histology were significantly normalized in the MRS7476-treated mice, but not liver fibrosis (no change in ACTA2 levels) or inflammation. Hepatic expression of ADORA3 in human NAFLD patients was 1.9-fold lower compared to normal controls. Adora3 expression determined by qPCR in primary mouse liver was associated with the stellate cells, and its mouse full body A_3AR knockout worsened liver markers of inflammation and steatosis. Thus, we have introduced a reversible prodrug strategy that enables water solubility and in vivo activity of masked A_3AR Agonists in models of two disease conditions.

  • design and in vivo activity of a3 Adenosine Receptor Agonist prodrugs
    Purinergic Signalling, 2020
    Co-Authors: R. Rama Suresh, Dilip K Tosh, Shanu Jain, Zhoumou Chen, Maren C. Podszun, Yaron Rotman, Daniela Salvemini, Kenneth A Jacobson

    Abstract:

    Prodrugs (MRS7422, MRS7476) of highly selective A3 Adenosine Receptor (AR) Agonists Cl-IB-MECA and MRS5698, respectively, were synthesized by succinylation of the 2′ and 3′ hydroxyl groups, and the parent, active drug was shown to be readily liberated upon incubation with liver esterases. The prodrug MRS7476 had greatly increased aqueous solubility compared with parent MRS5698 and was fully efficacious and with a longer duration than MRS7422 in reversing mouse neuropathic pain (chronic constriction injury model, 3 μmol/kg, p.o.), a known A3AR effect. MRS7476 (5 mg/kg, p.o., twice daily) was found to protect against non-alcoholic steatohepatitis (NASH) in the STAM mouse model, indicated by the NAFLD activity score. Hepatocyte ballooning, IL-10 production, and liver histology were significantly normalized in the MRS7476-treated mice, but not liver fibrosis (no change in ACTA2 levels) or inflammation. Hepatic expression of ADORA3 in human NAFLD patients was 1.9-fold lower compared to normal controls. Adora3 expression determined by qPCR in primary mouse liver was associated with the stellate cells, and its mouse full body A3AR knockout worsened liver markers of inflammation and steatosis. Thus, we have introduced a reversible prodrug strategy that enables water solubility and in vivo activity of masked A3AR Agonists in models of two disease conditions.

  • metabolic mapping of a3 Adenosine Receptor Agonist mrs5980
    Biochemical Pharmacology, 2015
    Co-Authors: Zhongze Fang, Dilip K Tosh, Naoki Tanaka, Haina Wang, Kristopher W Krausz, Robert D Oconnor, Kenneth A Jacobson, Frank J Gonzalez

    Abstract:

    ABSTRACT (1 S ,2 R ,3 S ,4 R ,5 S )-4-(2-((5-Chlorothiophen-2-yl)ethynyl)-6-(methylamino)-9 H -purin-9-yl)-2,3-dihydroxy- N -methylbicyclo[3.1.0]hexane-1-carboxamide ( MRS5980) is an A 3 AR selective Agonist containing multiple Receptor affinity- and selectivity-enhancing modifications and a therapeutic candidate drug for many inflammatory diseases. Metabolism-related poor pharmacokinetic behavior and toxicities are a major reason for drug R&D failure. Metabolomics with UPLC–MS was employed to profile the metabolism of MRS5980 and MRS5980-induced disruption of endogenous compounds. Recombinant drug-metabolizing enzymes screening experiment were used to determine the enzymes involved in MRS5980 metabolism. Analysis of lipid metabolism-related genes was performed to investigate the reason for MRS5980-induced lipid metabolic disorders. Unsupervised principal components analysis separated the control and MRS5980 treatment groups in feces, urine, and liver samples, but not in bile and serum. The major ions mainly contributing to the separation of feces and urine were oxidized MRS5980, glutathione (GSH) conjugates and cysteine conjugate (degradation product of the GSH conjugates) of MRS5980. The major ions contributing to the group separation of liver samples were phosphatidylcholines. In vitro incubation experiments showed the involvement of CYP3A enzymes in the oxidative metabolism of MRS5980 and direct GSH reactivity of MRS5980. The electrophilic attack by MRS5980 is a minor pathway and did not alter GSH levels in liver or liver histology, and thus may be of minor clinical consequence. Gene expression analysis further showed decreased expression of PC biosynthetic genes choline kinase a and b, which further accelerated conversion of lysophosphatidylcholine to phosphatidylcholines through increasing the expression of lysophosphatidylcholine acyltransferase 3. These data will be useful to guide rational design of drugs targeting A 3 AR, considering efficacy, metabolic elimination, and electrophilic reactivity.

Luiz Belardinelli – 2nd expert on this subject based on the ideXlab platform

  • effects of Adenosine and a selective a2a Adenosine Receptor Agonist on hemodynamic and thallium 201 and technetium 99m sestamibi biodistribution and kinetics
    Jacc-cardiovascular Imaging, 2009
    Co-Authors: Choukri Mekkaoui, Luiz Belardinelli, Farid Jadbabaie, Donald P Dione, David F Meoli, Kailasnath Purushothaman, Albert J Sinusas

    Abstract:

    Objectives The purpose of this study was to compare a selective A2A Adenosine Receptor Agonist (regadenoson) with Adenosine in clinically relevant canine models with regard to effects on hemodynamics and thallium-201 (201Tl) and technetium-99m (99mTc)-sestaMIBI biodistribution and kinetics. Background The clinical application of vasodilator stress for perfusion imaging requires consideration of the effects of these vasodilating agents on systemic hemodynamics, coronary flow, and radiotracer uptake and clearance kinetics. Methods Sequential imaging and arterial blood sampling was performed on control, anesthetized closed-chest canines (n = 7) to evaluate radiotracer biodistribution and kinetics after either a bolus administration of regadenoson (2.5 μg/kg) or 4.5-min infusion of Adenosine (280 μg/kg). The effects of regadenoson on coronary flow and myocardial radiotracer uptake were then evaluated in an open-chest canine model of a critical stenosis (n = 7). Results from ex vivo single-photon emission computed tomography were compared with tissue well-counting. Results The use of regadenoson compared favorably with Adenosine in regard to the duration and magnitude of the hemodynamic effects and the effect on 201Tl and 99mTc-sestaMIBI biodistribution and kinetics. The arterial blood clearance half-time was significantly faster for 99mTc-sestaMIBI (regadenoson: 1.4 ± 0.03 min; Adenosine: 1.5 ± 0.08 min) than for 201Tl (regadenoson: 2.5 ± 0.16 min, p Conclusions The bolus administration of regadenoson produced a hyperemic response comparable to a standard infusion of Adenosine. The biodistribution and clearance of both 201Tl and 99mTc-sestaMIBI during regadenoson were similar to Adenosine vasodilation. Ex vivo perfusion images under the most ideal conditions permitted detection of a critical stenosis, although 201Tl offered significant advantages over 99mTc-sestaMIBI for perfusion imaging during regadenoson vasodilator stress.

  • regadenoson a selective a2a Adenosine Receptor Agonist causes dose dependent increases in coronary blood flow velocity in humans
    Journal of Nuclear Cardiology, 2007
    Co-Authors: Hsiao D Lieu, John C Shryock, Gregory O Von Mering, Toufigh Gordi, Brent Blackburn, Ann Olmsted, Luiz Belardinelli, Richard A Kerensky

    Abstract:

    Background
    Regadenoson is a selective A2A Adenosine Receptor Agonist and vasodilator used to increase the heterogeneity of distribution of coronary blood flow during myocardial perfusion imaging. This study characterized the dose dependence of regadenoson-induced coronary hyperemia.

  • antilipolytic activity of a novel partial a1 Adenosine Receptor Agonist devoid of cardiovascular effects comparison with nicotinic acid
    Journal of Pharmacology and Experimental Therapeutics, 2007
    Co-Authors: Arvinder Dhalla, John C Shryock, Melissa Santikul, Michelle Smith, Meiyee Wong, Luiz Belardinelli

    Abstract:

    Elevated lipolysis and circulating free fatty acid (FFA) levels have been linked to the pathogenesis of insulin resistance. A 1 Adenosine Receptor Agonists are potent inhibitors of lipolysis. Several A 1 Agonists have been tested as potential antilipolytic agents; however, their effect on the cardiovascular system remains a potential problem for development of these agents as drugs. In the present study, we report that CVT-3619 [(2-{6-[((1 R ,2 R )-2-hydroxycyclopentyl) amino] purin9-yl} (4 S ,5 S ,2 R ,3 R )5-[(2fluorophenylthio) methyl] oxolane-3,4-diol)], a novel partial A 1 Receptor Agonist, significantly reduces circulating FFA levels without any effect on heart rate and blood pressure in awake rats. Rats were implanted with indwelling arterial and venous cannulas to obtain serial blood samples, record arterial pressure, and administer drug. CVT-3619 decreased FFA levels in a dose-dependent manner at doses from 1 up to 10 mg/kg. The FFA-lowering effect was blocked by the A 1 Receptor antAgonist, 1,3-dipropyl-8-cyclopentylxanthine. Triglyceride (TG) levels were also significantly reduced by CVT-3619 treatment in the absence and presence of Triton. Tachyphylaxis of the antilipolytic effect of CVT-3619 (1 mg/kg i.v. bolus) was not observed with three consecutive treatments. An acute reduction of FFA by CVT-3619 was not followed by a rebound increase of FFA as seen with nicotinic acid. The potency of insulin to decrease lipolysis was increased 4-fold ( p 1 Agonist that lowers circulating FFA and TG levels by inhibiting lipolysis. CVT-3619 has antilipolytic effects at doses that do not elicit cardiovascular effects.

Henry J Kaplan – 3rd expert on this subject based on the ideXlab platform

  • an a2b Adenosine Receptor Agonist promotes th17 autoimmune responses in experimental autoimmune uveitis eau via dendritic cell activation
    PLOS ONE, 2015
    Co-Authors: Mingjiazi Chen, Dongchun Liang, Hui Shao, Henry J Kaplan

    Abstract:

    We have recently reported that, although Adenosine Receptor (AR) Agonists have a suppressive effect on Th1 autoreactive T cells, their effect on Th17 autoreactive T cells and γδ T cells is stimulatory and this effect is mainly mediated via A2A Adenosine Receptors (A2ARs). In this study, we further demonstrate that treatment of C57BL/6 (B6) mice with a selective A2B Adenosine Receptor (A2BR) Agonist greatly enhanced the development of experimental autoimmune uveitis (EAU), whereas treatment with an A2BR antAgonist significantly ameliorated severity of EAU. The A2BR Agonist-treated mice showed augmented Th17, but not Th1, responses. Mechanistic studies showed that the A2BR Agonist-induced enhancement of the Th17 response was significantly lower when TCR-δ-/- mice received the same treatment and that transfer of γδ T cells into TCR-δ-/- mice partially restored this effect. We also showed that dendritic cells (DCs) from A2BR Agonist-treated mice showed a significantly increased ability to activate γδ T cells and Th17 autoreactive T cells. Thus, our previous studies have shown that, in EAU, activated γδ T cells possess greatly increased ability to enhance Th17 autoimmune responses. In the present study, we showed that exposure of DCs to A2BR Agonist facilitated γδ T cell activation, leading to augmented Th17 responses and progressive EAU development. Our results further support our previous finding that AR Agonists have distinct effects on Th1 and Th17 autoimmune responses.

  • anti inflammatory or proinflammatory effect of an Adenosine Receptor Agonist on the th17 autoimmune response is inflammatory environment dependent
    Journal of Immunology, 2014
    Co-Authors: Dongchun Liang, Mingjiazi Chen, Hui Shao, Henry J Kaplan

    Abstract:

    Adenosine is a key endogenous signaling molecule that regulates a wide range of physiological functions, including immune system function and inflammation. Studies have shown that Adenosine Receptor (AR) Agonists can be either anti-inflammatory or proinflammatory in immune responses and in inflammation, and the clarification of the mechanisms causing these opposing effects should provide a better guide for therapeutic intervention. Whereas previous studies mostly examined the effects of AR Agonists on Th1-type immune responses, in this study, we compared their effect on Th17 and Th1 autoimmune responses in experimental autoimmune uveitis, a mouse model of human uveitis induced by immunization with the human interphotoReceptor retinoid-binding protein peptides 1–20. We showed that injection of mice with a nonselective AR Agonist, 5′- N -ethylcarboxamidoAdenosine (NECA), at an early stage after immunization had an inhibitory effect on both Th1 and Th17 responses, whereas injection of the same amount of NECA at a late stage inhibited the Th1 response but had an enhancing effect on the Th17 response. We also showed that the effects of NECA on Th1 and Th17 responses were completely dissociated, that the enhancing effect of NECA on Th17 responses was modulated by γδ T cells, and that the response of γδ T cells to NECA was determined by their activation status. We conclude that the inflammatory environment has a strong impact on converting the effect of AR Agonist on the Th17 autoimmune response from anti-inflammatory to proinflammatory. Our observation should help in the designing of better AR-targeted therapies.