(E)-1,3-Dialkyl-7-methyl-8-(3,4,5-trimethoxystyryl)xanthines: potent and selective adenosine A2 antagonists

Shimada, Junichi; Suzuki, Fumio; Nonaka, Hiromi; Ishii, Akio; Ichikawa, S.

doi:10.1021/jm00090a027

Cited by 139 publications

(85 citation statements)

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“…But the most surprising results were obtained with KF 17837 which was presented as an A2-selective xanthine KF 17837 M-2=* (Shimada et al, 1992). At variance with the original work in the rat brain (Ki = 7.8 nM; Shimada et al, 1992) Jacobson et al (1993a) and in the present study.…”

Section: Discussioncontrasting

confidence: 60%

Effects of the new A₂ adenosine receptor antagonist 8FB‐PTP, an 8 substituted pyrazolo‐triazolo‐pyrimidine, on in vitro functional models

Dionisotti¹,

Conti²,

Sandoli³

et al. 1994

British J Pharmacology

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1 We have characterized the in vitro pharmacological profile of putative A2 adenosine antagonists, two non-xanthine compounds, 5-amino-8-(4-fluorobenzyl)-2-(2-furyl)-pyrazolo [4,3-e]-1,2,4-triazolo[l ,5-c] pyrimidine (8FB-PTP) and 5-amino-9-chloro-2-(2-furyl 1,2,4-triazolo [1,5-c] quinazoline (CGS 15943), and the xanthine derivative (E)7-methyl-8-(3,4-dimethoxystyryl)-1,3-dipropyl-xanthine (KF 17837).2 In binding studies on bovine brain, 8FB-PTP was the most potent (Ki = 0.074 nM) and selective (28 fold) drug on A2 receptors, whereas CGS 15943 and KF 17837 exhibited affinity in the low and high nanomolar range, respectively, and showed little selectivity. The data provided a basis to reduce, by further chemical modifications, the affinity at Al receptor and therefore enhance A2 receptor selectivity.

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Section: Discussioncontrasting

confidence: 60%

Effects of the new A₂ adenosine receptor antagonist 8FB‐PTP, an 8 substituted pyrazolo‐triazolo‐pyrimidine, on in vitro functional models

Dionisotti¹,

Conti²,

Sandoli³

et al. 1994

British J Pharmacology

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“…Stimulation of the A2,4 receptor by adenosine induces coronary and peripheral vasodilatation (Kusachi et al, 1983;Webb et al, 1990), while the Al receptor mediates cardiac depression (Olsson & Pearson, 1990). During the past few years selective and potent agonists and antagonists have been described for both receptor subtypes (Jacobson et al, 1992;Shimada et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic modelling of the haemodynamic effects of the A_2a adenosine receptor agonist CGS 21680C in conscious normotensive rats

Mathôt

Cleton

Soudijn

et al. 1995

British J Pharmacology

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1 The aim of the present investigation was to determine the relationship between the blood concentration and haemodynamic effects of the adenosine Au receptor agonist, CGS 21680C (the sodium salt of 2-p-(2-carboxyethyl)phenylethylamino-5'-N-ethylcarboxamidoadenosine) in conscious normotensive rats.2 Chronically cannulated rats were randomly assigned to three groups which received 300, 1000 or 3000 jLg kg-' (0.56, 1.9 or 5.6 pmol kg-') of CGS 21680C intravenously over 15 min. The mean arterial blood pressure (MAP) and heart rate (HR) were monitored continuously during the experiment and serial arterial blood samples were taken for analysis of drug concentration. The ratio MAP/HR was also calculated, which may reflect changes in total peripheral resistance on the assumption that no changes in stroke volume occur. 3 For each individual rat the reduction in mean arterial pressure was related to the blood concentration according to the sigmoidal E. model. The concentration-effect relationships were consistent for the different treatment groups. The potency based on free drug concentrations (ECm,u) was 5.8 ng ml' (11 nM) (mean ± s.e.; n = 19) and correlated well with the reported adenosine Au4 receptor affinity (Ki 19 nM). In comparison with the reduction in blood pressure, CGS 21680C exhibited a greater potency for the reduction of the ratio MAP/HR. 4 It is concluded that estimates can be obtained for the potency and intrinsic activity of adenosine Au receptor agonists in vivo by pharmacokinetic-pharmacodynamic analysis of mean arterial pressure data in a rat model. In future studies, total peripheral resistance may also be useful as a pharmacodynamic parameter for A,4 activation, provided that possible changes of the stroke volume are also assessed.

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“…An isothiocyanate derivative (1,3,7-trimethyl-8-(3-isothiocyanato-styryl)xanthine, ISC, 2) in the A 2 -selective, 8-styrylxanthine series of adenosine antagonists [Shimada et al, 1992;Jacobson et al, 1993] was prepared as a potential receptor affinity label. It was synthesized by reaction of the corresponding 3-amino derivative , 1, with thiophosgene ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Binding site-directed affinity labels for A 1 -receptors (agonists and antagonists) and A 2a -receptors (agonists) have been synthesized based on a functionalized congener approach. Recently, 8-styrylxanthine derivatives that act as A 2a -selective adenosine antagonists have been reported [Shimada et al, 1992]. We now introduce an 8-styrylxanthine isothiocyanate derivative that acts as a selective irreversible inhibitor of binding to A 2a -receptors.…”

Section: Introductionmentioning

confidence: 99%

8‐(3‐Isothiocyanatostyryl)caffeine is a selective, irreversible inhibitor of striatal A₂‐Adenosine receptors

Gallo‐Rodriguez

Jacobson

1993

Drug Development Research

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Abstract8-(3-Isothiocyanatostyryl)caffeine (ISC) was synthesized and shown to inhibit selectively the binding of [ 3 H]CGS 21680 (an A 2a -selective agonist) at adenosine receptors in striatal membranes. The K i value at A 2a -receptors was found to be 110 nM (rat), with selectivity ratios for A 2a versus A 1 -receptors in rat, guinea pig, bovine, and rabbit striatum of >100-fold. Preincubation of membranes with ISC caused a dose-dependent, irreversible antagonism of the binding of [ 3 H]CGS 21680, with an IC 50 value of 3 μM. The irreversibility is likely due to the presence of the chemically reactive isothiocyanate group, since the binding of the corresponding analogue in which the isothiocyanate was replaced with a chloro group was completely reversible. The potency of ISC to irreversibly inhibit the binding of

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(E)-1,3-Dialkyl-7-methyl-8-(3,4,5-trimethoxystyryl)xanthines: potent and selective adenosine A2 antagonists

Cited by 139 publications

References 2 publications

Effects of the new A₂ adenosine receptor antagonist 8FB‐PTP, an 8 substituted pyrazolo‐triazolo‐pyrimidine, on in vitro functional models

Effects of the new A₂ adenosine receptor antagonist 8FB‐PTP, an 8 substituted pyrazolo‐triazolo‐pyrimidine, on in vitro functional models

Pharmacokinetic modelling of the haemodynamic effects of the A_2a adenosine receptor agonist CGS 21680C in conscious normotensive rats

8‐(3‐Isothiocyanatostyryl)caffeine is a selective, irreversible inhibitor of striatal A₂‐Adenosine receptors

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(E)-1,3-Dialkyl-7-methyl-8-(3,4,5-trimethoxystyryl)xanthines: potent and selective adenosine A2 antagonists

Cited by 139 publications

References 2 publications

Effects of the new A2 adenosine receptor antagonist 8FB‐PTP, an 8 substituted pyrazolo‐triazolo‐pyrimidine, on in vitro functional models

Effects of the new A2 adenosine receptor antagonist 8FB‐PTP, an 8 substituted pyrazolo‐triazolo‐pyrimidine, on in vitro functional models

Pharmacokinetic modelling of the haemodynamic effects of the A2a adenosine receptor agonist CGS 21680C in conscious normotensive rats

8‐(3‐Isothiocyanatostyryl)caffeine is a selective, irreversible inhibitor of striatal A2‐Adenosine receptors

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Product

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Effects of the new A₂ adenosine receptor antagonist 8FB‐PTP, an 8 substituted pyrazolo‐triazolo‐pyrimidine, on in vitro functional models

Effects of the new A₂ adenosine receptor antagonist 8FB‐PTP, an 8 substituted pyrazolo‐triazolo‐pyrimidine, on in vitro functional models

Pharmacokinetic modelling of the haemodynamic effects of the A_2a adenosine receptor agonist CGS 21680C in conscious normotensive rats

8‐(3‐Isothiocyanatostyryl)caffeine is a selective, irreversible inhibitor of striatal A₂‐Adenosine receptors