PD 115,199: An antagonist ligand for adenosine A2 receptors

Bruns, Robert F.; Fergus, James H.; Badger, Edward W.; Bristol, James A.; Santay, Lisa A.; Hays, Samuel P.

doi:10.1007/bf00165038

Cited by 94 publications

(75 citation statements)

References 9 publications

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“…The shift (4.1) in the concentration-response curve for R-PIA caused by DPCPX (2.5 nM) is consistent with a Ki value for the xanthine of about 0.8 nm, which is of the same order as the Ki value (0.54 nM) obtained for DPCPX in experiments recording nerve-evoked twitch responses from phrenic nerve-diaphragm preparations partially inhibited with tubocurarine and is also of the same order as the K, value for this xanthine at A1 adenosine receptors (Bruns et al, 1987;Lohse et al, 1987 (Hutchison et al, 1989) it seems likely that the excitatory effect of the adenosine analogues on [3H]-acetylcholine release is mediated by an A2 adenosine receptor. This is supported by the observations that the excitatory effects of NECA and CGS 21680C were antagonized by PD 115,199.…”

supporting

confidence: 83%

“…This is supported by the observations that the excitatory effects of NECA and CGS 21680C were antagonized by PD 115,199. Though this xanthine is poorly selective for A2 or A1 adenosine receptors, it is a potent antagonist of the A2 adenosine receptors when the A1 adenosine receptors are blocked by DPCPX (Bruns et al, 1987). Excitatory effects of adenosine analogues on acetylcholine release, probably mediated by A2 adenosine receptors were reported recently (Barry, 1990;Brown et al, 1990).…”

mentioning

confidence: 92%

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Inhibitory and excitatory effects of adenosine receptor agonists on evoked transmitter release from phrenic nerve endings of the rat

Correia-de-Sá

Sebastião

Ribeiro

1991

British J Pharmacology

135

102

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1 The effects of the adenosine analogues, 5'-N-ethyl-carboxamide adenosine (NECA), R-N6-phenylisopropyladenosine (R-PIA), 2-chloroadenosine (CADO), and CGS 21680C on electrically evoked tritium outflow from preparations loaded with [3H]-choline and on evoked endplate potentials (e.p.ps), as well as the ability of the xanthines, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) and PD 115,199 to antagonize the effects of the adenosine analogues, were investigated in phrenic nerve-diaphragm preparations. 2 NECA, R-PIA and CADO decreased, in a concentration-dependent manner, the evoked tritium outflow from preparations loaded with [3H]-choline. NECA and R-PIA were about equipotent and more potent than CADO. 3 DPCPX shifted to the right in a near parallel fashion the concentration-response curve for the inhibitory effect of R-PIA on evoked tritium outflow. 4 In the presence of DPCPX, NECA increased, rather than decreased, evoked tritium outflow. PD 115,199 antagonized, in a concentration-dependent manner, this excitatory effect of NECA. 5 CGS 21680C, in low nanomolar concentrations, increased evoked tritium outflow, an effect also antagonized by PD 115,199. 6 CGS 21680C increased, and R-PIA decreased, the amplitude of e.p.ps recorded from preparations paralysed with tubocurarine. Both effects could be observed in the same endplate.7 It is concluded that both inhibitory (probably Al) and excitatory (probably A2) adenosine receptors coexist at the rat neuromuscular junction, modulating the evoked release of acetylcholine.

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supporting

confidence: 83%

mentioning

confidence: 92%

Inhibitory and excitatory effects of adenosine receptor agonists on evoked transmitter release from phrenic nerve endings of the rat

Correia-de-Sá

Sebastião

Ribeiro

1991

British J Pharmacology

135

102

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“…PD1 15199 however shows little selectivity for A2a relative to Al receptors (2.4 fold, Bruns et al, 1987b). ZM 241385 had no additional pharmacological effects at concentrations which blocked A2a adenosine receptors.…”

Section: Discussionmentioning

confidence: 96%

“…The xanthine, PD1 15199 (1,3 dipropyl-8-N-[2-dimethylamino) ethyl]-N-methyl-4-2, 3,6, 7-tetrahydro-2,6-dioxo) -benzenesulphonamidexanthine), although having higher affinity for the A2a binding site than the A2b binding site, is equipotent at A2a and A1 binding sites (Bruns et al, 1987b). PD1 16948 (8-cyclopentyl-1-3-dipropylxanthine) has higher affinity for the A1 receptor than for A2a binding sites in rat brain studies (Bruns et al, 1987a,b;Jarvis et al, 1989) and clearly demonstrated A1-selective antagonism in guinea-pig isolated tissues (Collis et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

The in vitro pharmacology of ZM 241385, a potent, non‐xanthine, A_2a selective adenosine receptor antagonist

Poucher

Keddie

Singh

et al. 1995

British J Pharmacology

331

222

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1 This paper describes the in vitro pharmacology of ZM 241385 (4-(2-[7-amino-2-(2-furyl) antagonized vasodilatation of the coronary bed produced by 2-chloroadenosine (2-CADO) and 2-[p-(2-carboxyethyl) phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680) with pA2 values of 8.57 (c.l., 8.45-8.68) and 9.02 (c.l., 8.79-9.24) respectively. 3 ZM 241385 had low potency at A2b receptors and antagonized the relaxant effects of adenosine in the guinea-pig aorta with a pA2 of 7.06, (c.l., 6.92-7.19). 4 ZM 241385 had a low affinity at A1 receptors. In rat cerebral cortex membranes it displaced tritiated R-phenylisopropyladenosine (R-PIA) with a pIC50 of 5.69 (c.l., 5.57-5.81). ZM 241385 antagonized the bradycardic action of 2-CADO in guinea-pig atria with a pA2 of 5.95 (c.l., 5.72-6.18). 5 ZM 241385 had low affinity for A3 receptors. At cloned rat A3 receptors expressed in chinese hamster ovary cells, it displaced iodinated aminobenzyl-5'-N-methylcarboxamido adenosine (AB-MECA) with a pIC50 of 3.82 (c.l., 3.67-4.06). 6 ZM 241385 had no significant additional pharmacological effects on the isolated tissues used in these studies at concentrations three orders of magnitude greater than those which block A2a receptors. At 10 gM it displayed only minor inhibition of the bradycardic effects in guinea-pig atria to some concentrations of carbachol. At 10 gM, ZM 241385 had a small inhibitory effect on relaxant effects of isoprenaline in guinea-pig aortae but no effect on sodium nitrite-induced relaxation. ZM 241385 (100 gM) was without effect on phenylephrine-induced tone in guinea-pig aortae. 7 ZM 241385 (10 gM) had no inhibitory effect on rat hepatocyte phosphodiesterase types I, II, III and IV but caused a small inhibition of the calcium calmodulin-activated type I enzyme. 8 ZM 241385 is the most selective adenosine A2a receptor antagonist yet described and is therefore a useful tool for characterization of responses mediated by A2 adenosine receptors.

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“…CGS21680 (Hutchison et al, , 1990Jarvis et al, 1989) and an iodinatable functionalized congener related to it, PAPA-APEC (Barrington et al, 1989;Jacobson et al, 1989c), are high affinity agonist radioligands that are selective for A 2 -receptors. There are only two reports of adenosine antagonists, namely XAC and PD115,199, as radioligands at A 2 -adenosine receptors (Ukena et al, 1986a;Bruns et al, 1987). Both XAC and PD115,199 bind to A 2 -receptors under the proper circumstances, but neither ligand is A 2 -selective.…”

Section: Discussionmentioning

confidence: 99%

[3H]XAC (xanthine amine congener) is a radioligand for A2-adenosine receptors in rabbit striatum

Stiles

1991

Neurochemistry International

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The intrinsic affinity of 8-phenylxanthine analogs at striatal A 2 -adenosine receptors is highly species dependent. [ 3 H]XAC (8-[2-aminoethyl[amino[carbonyl[methyl[oxyphenyl]]]]]-1,3-dipropylxan-thine), although A 1 -selective in the rat brain, binds to A 2 receptors in rabbit striatal membranes with sufficiently high affinity to serve as a radioligand. In the presence of 50 nM CPX (8-cyclopentyl-1,3-dipropylxanthine), an A 1 -selective antagonist added to eliminate binding to A 1 receptors, [ 3 H]XAC exhibits saturable, specific binding (70% of total) to A 2 sites with a K d of 3.8 nM and a B max of 1.23 pmol/mg protein. At 24°C, the association and dissociation rate constants were 0.13 min −1 nM −1 and 0.36 min −1 , respectively. Binding was performed for 1 h, with nonspecific binding defined in the presence of 100 μM NECA (N-ethylcarboxamidoadenosine). The potency order for antagonists against 1 nM [ 3 H]XAC at rabbit A 2 -receptors was XAC ≈ N α -Me-XAC ≫ CPX = XCC > 1,3-dipropyl-8-p-sulfophenylxanthine > PSPT. The relative potency order for agonists was CGS ≈ NECA > APEC [ = 2-(aminoethylaminocarbonylethylphenylethylamino)-NECA] > PAPA-APEC > ADAC > R-PIA (N 6 -phenylisopropyladenosine) > S-PIA.The ability to characterize central A 2 -adenosine receptors using an antagonist ligand that is chemically functionalized offers the possibility to design affinity labeling probes for this receptor subtype in the brain, similar to those antagonist probes already developed for A 1 -receptors. The results also suggest that affinity columns containing chemically immobilized XAC may be used for isolating central A 2 -adenosine receptors from rabbit striatum.Adenosine, acting as a neuromodulator, inhibits the release of numerous stimulatory neurotransmitters, including glutamate, norepinephrine, serotonin and acetylcholine (Fredholm and Dunwiddie, 1988). Adenosine agonists acting in vivo via a central mechanism cause a dramatic depression of locomotor activity (Nikodijevic et al., 1990). 1,3-Dialkylxan-thines act as antagonists of adenosine at A 1 -and A 2 -adenosine receptor subtypes (Ramkumar et al., 1988). X A C (8-[4-[[[(2-aminoethyl)amino]carbonyl]-methyl]-oxy]phenyl]-1,3-dipropylxanthine), a xanthine amine congener (Jacobson et al., 1986), is a potent adenosine antagonist with an A 1 -selectivity ratio in the rat of 20-to 80-fold. *Author to whom all correspondence should be addressed at: Bldg 8A, Rm BlA-17, National Institutes of Health, Bethesda, MD 20892, U.S.A. A large species-dependent variation in the potencies of certain substituted purine derivatives at A 1 and at A 2 receptors has been noted. For example, a given 8-phenylxanthine or N 6 -phenyladenosine derivative may have affinities for central A 1 -receptors ranging over several orders of magnitude depending on species (Ukena et al., 1986b). Typically, the speciesdependent order of potency for 8-phenylxanthines at A 1 -receptors is: calf > rat > guinea pig, human. At A 2 -receptors, the K i -values for 1,3-diethyl-8-phenyl-xanthine (DPX) were sh...

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PD 115,199: An antagonist ligand for adenosine A2 receptors

Cited by 94 publications

References 9 publications

Inhibitory and excitatory effects of adenosine receptor agonists on evoked transmitter release from phrenic nerve endings of the rat

Inhibitory and excitatory effects of adenosine receptor agonists on evoked transmitter release from phrenic nerve endings of the rat

The in vitro pharmacology of ZM 241385, a potent, non‐xanthine, A_2a selective adenosine receptor antagonist

[3H]XAC (xanthine amine congener) is a radioligand for A2-adenosine receptors in rabbit striatum

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PD 115,199: An antagonist ligand for adenosine A2 receptors

Cited by 94 publications

References 9 publications

Inhibitory and excitatory effects of adenosine receptor agonists on evoked transmitter release from phrenic nerve endings of the rat

Inhibitory and excitatory effects of adenosine receptor agonists on evoked transmitter release from phrenic nerve endings of the rat

The in vitro pharmacology of ZM 241385, a potent, non‐xanthine, A2a selective adenosine receptor antagonist

[3H]XAC (xanthine amine congener) is a radioligand for A2-adenosine receptors in rabbit striatum

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The in vitro pharmacology of ZM 241385, a potent, non‐xanthine, A_2a selective adenosine receptor antagonist