2-Alkynyl-8-aryladenines possessing an amide moiety: their synthesis and structure–activity relationships of effects on hepatic glucose production induced via agonism of the A2B adenosine receptor

Asano, Osamu; Kawata, Tsutomu; Inoue, Takashi; Horizoe, Tatsuo; Yasuda, Nobuyuki; Nagata, Kaya; Murakami, Manabu; Nagaoka, Junsaku; Kobayashi, Seiichi

doi:10.1016/s0968-0896(01)00201-2

Cited by 32 publications

(9 citation statements)

References 17 publications

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“…Previous studies have shown that the stable nonselective adenosine analog NECA stimulates glucose production by hepatocytes (34). In the current study we show that oral gavage with NECA acutely increases fasting glucose levels and strongly inhibits glucose disposal.…”

Section: Discussionmentioning

confidence: 99%

Links Between Insulin Resistance, Adenosine A2B Receptors, and Inflammatory Markers in Mice and Humans

et al. 2011

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OBJECTIVETo determine the mechanisms by which blockade of adenosine A2B receptors (A2BRs) reduces insulin resistance.RESEARCH DESIGN AND METHODSWe investigated the effects of deleting or blocking the A2BR on insulin sensitivity using glucose tolerance tests (GTTs) and hyperinsulinemic-euglycemic clamps in mouse models of type 2 diabetes. The effects of diabetes on A2BR transcription and signaling were measured in human and mouse macrophages and mouse endothelial cells. In addition, tag single nucleotide polymorphisms (SNPs) in ∼42 kb encompassing the A2BR gene, ADORA2B, were evaluated for associations with markers of diabetes and inflammation.RESULTSTreatment of mice with the nonselective adenosine receptor agonist 5′-N-ethylcarboxamidoadensoine (NECA) increased fasting blood glucose and slowed glucose disposal during GTTs. These responses were inhibited by A2BR deletion or blockade and minimally affected by deletion of A1Rs or A2ARs. During hyperinsulinemic-euglycemic clamp of diabetic KKAY mice, A2BR antagonism increased glucose infusion rate, reduced hepatic glucose production, and increased glucose uptake into skeletal muscle and brown adipose tissue. Diabetes caused a four- to sixfold increase in A2BR mRNA in endothelial cells and macrophages and resulted in enhanced interleukin (IL)-6 production in response to NECA due to activation of protein kinases A and C. Five consecutive tag SNPs in ADORA2B were highly correlated with IL-6 and C-reactive protein (CRP). Diabetes had a highly significant independent effect on variation in inflammatory markers. The strength of associations between several ADORA2B SNPs and inflammatory markers was increased when accounting for diabetes status.CONCLUSIONSDiabetes affects the production of adenosine and the expression of A2BRs that stimulate IL-6 and CRP production, insulin resistance, and the association between ADORA2B SNPs and inflammatory markers. We hypothesize that increased A2BR signaling in diabetes increases insulin resistance in part by elevating proinflammatory mediators. Selective A2BR blockers may be useful to treat insulin resistance.

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Section: Discussionmentioning

confidence: 99%

Links Between Insulin Resistance, Adenosine A2B Receptors, and Inflammatory Markers in Mice and Humans

et al. 2011

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“…Harada et al proposed 2-alkynyl-8-aryl-9-methyladenine derivatives and 2-alkynyl-8-aryladenine derivatives bearing an amide moiety at the 9-position [17,59] as candidate hypoglycemic agents. Starting from the first results on compound 36 [17], which displayed an interesting affinity at A 2B AR (K i = 23 nM), the authors synthesized many amide derivatives [59], obtaining the best results with the benzamide 37, 15-fold more active than the corresponding 9-methyl derivative on the A 2B subtype ( Table 8).…”

Section: Non-xanthinementioning

confidence: 99%

“…Starting from the first results on compound 36 [17], which displayed an interesting affinity at A 2B AR (K i = 23 nM), the authors synthesized many amide derivatives [59], obtaining the best results with the benzamide 37, 15-fold more active than the corresponding 9-methyl derivative on the A 2B subtype ( Table 8).…”

Section: Non-xanthinementioning

confidence: 99%

A2B Receptor Ligands: Past, Present and Future Trends

Ortore¹,

Martinelli²

2010

CTMC

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A(2B) adenosine receptors have been investigated in recent years as potential target for the treatment of different pathologies. The involvement of this receptor in processes such as interleukins secretion, Ca(2+) mobilization, hepatic glucose regulation, tumor vascularisation, and cardioprotection have stimulated many researchers to develop specific agonists and antagonists. For many years, the lack of potent and selective A(2B) ligands precluded a deep exploration of their therapeutic prospective; at present, much progress in the field of antagonists led to preclinical studies for different compounds. Less populated is the universe of A(2B) agonists, but really promising for the involvement in ischemic preconditioning. A summary of the most significant advancements in the synthesis of new compounds and of the principal structure activity relationships is reported. The xanthine-based A(2B) antagonists currently show the better profile of affinity and selectivity, as CVT-6883 (CVT-Therapeutics: K(i(A2B))=22 nM, and selectivity higher than 50-fold over other subtypes), MRE-2029-F20 (Baraldi's group: K(i(A2B))=5.5 nM, selectivity >180 fold), LAS38096 (Almirall Prodesfarma: K(i(A2B))=17 nM, selectivity >60 fold), OSIP339391 (OSI Pharmaceuticals: K(i(A2B))=0.5 nM, selectivity >80 fold), PSB601 (Bonn University: K(i(A2B))=3.6 nM, selectivity >140 fold) and the deazaxanthine 32 of Carotti's group (K(i(A2B))=11 nM, selectivity >90 fold). Other recently emerging scaffolds with promising biological profiles are described. With regard to the agonists, many research groups are involved in the discovery of useful agonist radioligands, but the only example of potent and rather selective A(2B) agonists are compound 65, recently synthesized, and BAY-60-6583, that is under preclinical phase investigation.

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“…15 A 1 receptor agonists also decrease glucose and amino acid uptake in rat skeletal muscle. 11 Since A 2B -receptor antagonists may reduce hepatic glucose production 16 and may inhibit retinal angiogenesis, 17 a combined A 1 -and A 2B receptor antagonist, BG-9928 was positively tested in an animal model of metabolic syndrome (ZDF-1 rat). 18 Mainly an A 1 receptor antagonist should be useful for the treatment of diabetes.…”

Section: Rbmentioning

confidence: 99%

Modulation of insulin release by adenosine A₁ receptor agonists and antagonists in INS‐1 cells: The possible contribution of ⁸⁶Rb⁺ efflux and ⁴⁵Ca²⁺ uptake

Töpfer¹,

Burbiel²,

Müller³

et al. 2008

Cell Biochemistry & Function

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Due to the lack of specific agonists and antagonists the role of adenosine receptor subtypes with respect to their effect on the insulin secretory system is not well investigated. The A1 receptor may be linked to different 2nd messenger systems, i.e. cAMP, K+- and 45Ca2+ channel activity. Partial A1 receptor agonists are going to be developed in order to improve diabetes (increase in insulin sensitivity, lowering of FFA and triglycerides). In this study newly synthesized selective A1 receptor agonists and antagonists were investigated thereby integrating three parameters, insulin release (RIA), 45Ca2+ uptake and 86Rb+ efflux (surrogate for K+ efflux) of INS-1 cells, an insulin secretory cell line. The presence of A1-receptors was demonstrated by Western blotting. The receptor nonselective adenosine analogue NECA (5-N-ethylcarboxyamidoadenosine) at high concentration (10 microM) had no effect on insulin release and 45Ca2+ uptake which could be interpreted as the sum of effects mediated by mutual antagonistic adenosine receptor subtypes. However, an inhibitory effect mediated by A1 receptor agonism was detected at 10 nM NECA and could be confirmed by adding the A1 receptor antagonist PSB-36 (1-butyl-8-(3-noradamantyl)-3-(3-hydroxy-propyl)xanthine). NECA inhibited 86Rb+ efflux which, however, did not fit with the simultaneous inhibition of insulin secretion. The selective A1 receptor agonist CHA (N6-cyclohexyladenosine) inhibited insulin release; the simultaneously increased Ca2+ uptake (nifedipine dependent) and inhibition of 86Rb+ efflux did not fit the insulin release data. The CHA effect (even the maximum effect at 50 microM) can be increased by 10 microM NECA indicating that CHA and NECA have nonspecific and physiologically non-relevant effects on 86Rb+ efflux in addition to their A1-receptor interaction. Since PSB-36 did not influence the NECA-induced inhibition of 86Rb+ efflux, the NECA effect is not mediated by potassium channel-linked A1 receptors. The nonselective adenosine receptor antagonist caffeine increased insulin release which was reversed by CHA as expected when hypothesizing that both act via A1 receptors in this case. In conclusion, stimulation of A1 receptors by receptor selective and nonselective compounds reduced insulin release which is not coupled to opening of potassium channels (86Rb+ efflux experiments) or inhibition of calcium channels (45Ca2+ uptake experiments). It may be expected that of all pleiotropic 2nd messengers, the cAMP system (not tested here) is predominant for A1 receptor effects and the channel systems (K+ and Ca2+) are of minor importance and do not contribute to insulin release though being coupled to the receptor in other tissues.

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2-Alkynyl-8-aryladenines possessing an amide moiety: their synthesis and structure–activity relationships of effects on hepatic glucose production induced via agonism of the A2B adenosine receptor

Cited by 32 publications

References 17 publications

Links Between Insulin Resistance, Adenosine A2B Receptors, and Inflammatory Markers in Mice and Humans

Links Between Insulin Resistance, Adenosine A2B Receptors, and Inflammatory Markers in Mice and Humans

A2B Receptor Ligands: Past, Present and Future Trends

Modulation of insulin release by adenosine A₁ receptor agonists and antagonists in INS‐1 cells: The possible contribution of ⁸⁶Rb⁺ efflux and ⁴⁵Ca²⁺ uptake

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2-Alkynyl-8-aryladenines possessing an amide moiety: their synthesis and structure–activity relationships of effects on hepatic glucose production induced via agonism of the A2B adenosine receptor

Cited by 32 publications

References 17 publications

Links Between Insulin Resistance, Adenosine A2B Receptors, and Inflammatory Markers in Mice and Humans

Links Between Insulin Resistance, Adenosine A2B Receptors, and Inflammatory Markers in Mice and Humans

A2B Receptor Ligands: Past, Present and Future Trends

Modulation of insulin release by adenosine A1 receptor agonists and antagonists in INS‐1 cells: The possible contribution of 86Rb+ efflux and 45Ca2+ uptake

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Modulation of insulin release by adenosine A₁ receptor agonists and antagonists in INS‐1 cells: The possible contribution of ⁸⁶Rb⁺ efflux and ⁴⁵Ca²⁺ uptake