1,3-Dipropyl-8-[2-(5,6-epoxy)norbornyl]xanthine, a potent, specific and selective A1 adenosine receptor antagonist in the guinea pig heart and brain and in DDT1MF-2 cells

L. Belardinelli, J. C. Shryock, Y. Zhang, P. J. Scammells, R. Olsson, D. Dennis, P. Milner, J. Pfister, S. P. Baker

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Abstract

The objective of this study was to characterize the adenosine receptor (AdoR) antagonistic properties of a newly synthesized alkylxanthine, 1,3- dipropyl-8[2-(5,6-epoxy)norbornyl]xanthine (ENX), and compare them to those of 1,3-dipropyl-8-(cyclopentyl)xanthine (CPX), 1,3-dipropyl-8-(3- noradamantyl)xanthine (NAX) and (±)-N6-endo-norbornan-2-yl-9-methyladenine (N-0861). The potencies and selectivities of ENX, CPX, NAX and N-0861 were determined by functional studies of guinea pig isolated perfused hearts, and by radioligand binding assays for A1 and A(2a) AdoRs in the guinea pig forebrain and striatum. ENX competitively antagonized A1 AdoR-mediated prolongations of atrioventricular nodal conduction time caused by Ado or by 2-chloro-N6-cyclopentyladenosine, but not those caused by carbachol (0.14 μM) or MgCl2 (3 mM). Schild analysis of 2-chloro-N6-cyclopentyladenosine- antagonist competition curves yielded pA2 values for ENX, CPX and NAX of 8.45 ± 0.19, 8.55 ± 0.28 and 8.79 ± 0.15, respectively. ENX (30 μM) and N-0861 (30 μM) did not attenuate the A2 AdoR-mediated increase in coronary conductance caused by adenosine. CPX and NAX attenuated the coronary vasodilation caused by adenosine with IC50 values of 1.5 and 7.1 μM, respectively. Radioligand binding assays revealed that ENX, CPX and NAX and N-0861 had a 400-, 209-, 110- and 10-fold greater affinity, respectively, for A1 than for A(2a) AdoRs of guinea pig brain membranes. Thus, ENX was equipotent with CPX and NAX and more potent than N-0861 (pA2 = 6.2) as an antagonist at A1 AdoRs, but had lower affinity for A2 AdoRs in guinea pig hearts and brain striatum than did either CPX or NAX. In DDT1 MF-2 cells, all three alkylxanthines had similar affinities for A1 AdoRs, whereas the affinity of N-0861 for A1 AdoRs was significantly lower. ENX appears to be the most A1 AdoR subtype-selective of the alkylxanthine class of AdoR antagonists reported to date.
Original languageEnglish
Pages (from-to)1167-1176
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume275
Issue number3
Publication statusPublished - 1 Dec 1995

Cite this

Belardinelli, L. ; Shryock, J. C. ; Zhang, Y. ; Scammells, P. J. ; Olsson, R. ; Dennis, D. ; Milner, P. ; Pfister, J. ; Baker, S. P. / 1,3-Dipropyl-8-[2-(5,6-epoxy)norbornyl]xanthine, a potent, specific and selective A1 adenosine receptor antagonist in the guinea pig heart and brain and in DDT1MF-2 cells. In: Journal of Pharmacology and Experimental Therapeutics. 1995 ; Vol. 275, No. 3. pp. 1167-1176.
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abstract = "The objective of this study was to characterize the adenosine receptor (AdoR) antagonistic properties of a newly synthesized alkylxanthine, 1,3- dipropyl-8[2-(5,6-epoxy)norbornyl]xanthine (ENX), and compare them to those of 1,3-dipropyl-8-(cyclopentyl)xanthine (CPX), 1,3-dipropyl-8-(3- noradamantyl)xanthine (NAX) and (±)-N6-endo-norbornan-2-yl-9-methyladenine (N-0861). The potencies and selectivities of ENX, CPX, NAX and N-0861 were determined by functional studies of guinea pig isolated perfused hearts, and by radioligand binding assays for A1 and A(2a) AdoRs in the guinea pig forebrain and striatum. ENX competitively antagonized A1 AdoR-mediated prolongations of atrioventricular nodal conduction time caused by Ado or by 2-chloro-N6-cyclopentyladenosine, but not those caused by carbachol (0.14 μM) or MgCl2 (3 mM). Schild analysis of 2-chloro-N6-cyclopentyladenosine- antagonist competition curves yielded pA2 values for ENX, CPX and NAX of 8.45 ± 0.19, 8.55 ± 0.28 and 8.79 ± 0.15, respectively. ENX (30 μM) and N-0861 (30 μM) did not attenuate the A2 AdoR-mediated increase in coronary conductance caused by adenosine. CPX and NAX attenuated the coronary vasodilation caused by adenosine with IC50 values of 1.5 and 7.1 μM, respectively. Radioligand binding assays revealed that ENX, CPX and NAX and N-0861 had a 400-, 209-, 110- and 10-fold greater affinity, respectively, for A1 than for A(2a) AdoRs of guinea pig brain membranes. Thus, ENX was equipotent with CPX and NAX and more potent than N-0861 (pA2 = 6.2) as an antagonist at A1 AdoRs, but had lower affinity for A2 AdoRs in guinea pig hearts and brain striatum than did either CPX or NAX. In DDT1 MF-2 cells, all three alkylxanthines had similar affinities for A1 AdoRs, whereas the affinity of N-0861 for A1 AdoRs was significantly lower. ENX appears to be the most A1 AdoR subtype-selective of the alkylxanthine class of AdoR antagonists reported to date.",
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1,3-Dipropyl-8-[2-(5,6-epoxy)norbornyl]xanthine, a potent, specific and selective A1 adenosine receptor antagonist in the guinea pig heart and brain and in DDT1MF-2 cells. / Belardinelli, L.; Shryock, J. C.; Zhang, Y.; Scammells, P. J.; Olsson, R.; Dennis, D.; Milner, P.; Pfister, J.; Baker, S. P.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 275, No. 3, 01.12.1995, p. 1167-1176.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - 1,3-Dipropyl-8-[2-(5,6-epoxy)norbornyl]xanthine, a potent, specific and selective A1 adenosine receptor antagonist in the guinea pig heart and brain and in DDT1MF-2 cells

AU - Belardinelli, L.

AU - Shryock, J. C.

AU - Zhang, Y.

AU - Scammells, P. J.

AU - Olsson, R.

AU - Dennis, D.

AU - Milner, P.

AU - Pfister, J.

AU - Baker, S. P.

PY - 1995/12/1

Y1 - 1995/12/1

N2 - The objective of this study was to characterize the adenosine receptor (AdoR) antagonistic properties of a newly synthesized alkylxanthine, 1,3- dipropyl-8[2-(5,6-epoxy)norbornyl]xanthine (ENX), and compare them to those of 1,3-dipropyl-8-(cyclopentyl)xanthine (CPX), 1,3-dipropyl-8-(3- noradamantyl)xanthine (NAX) and (±)-N6-endo-norbornan-2-yl-9-methyladenine (N-0861). The potencies and selectivities of ENX, CPX, NAX and N-0861 were determined by functional studies of guinea pig isolated perfused hearts, and by radioligand binding assays for A1 and A(2a) AdoRs in the guinea pig forebrain and striatum. ENX competitively antagonized A1 AdoR-mediated prolongations of atrioventricular nodal conduction time caused by Ado or by 2-chloro-N6-cyclopentyladenosine, but not those caused by carbachol (0.14 μM) or MgCl2 (3 mM). Schild analysis of 2-chloro-N6-cyclopentyladenosine- antagonist competition curves yielded pA2 values for ENX, CPX and NAX of 8.45 ± 0.19, 8.55 ± 0.28 and 8.79 ± 0.15, respectively. ENX (30 μM) and N-0861 (30 μM) did not attenuate the A2 AdoR-mediated increase in coronary conductance caused by adenosine. CPX and NAX attenuated the coronary vasodilation caused by adenosine with IC50 values of 1.5 and 7.1 μM, respectively. Radioligand binding assays revealed that ENX, CPX and NAX and N-0861 had a 400-, 209-, 110- and 10-fold greater affinity, respectively, for A1 than for A(2a) AdoRs of guinea pig brain membranes. Thus, ENX was equipotent with CPX and NAX and more potent than N-0861 (pA2 = 6.2) as an antagonist at A1 AdoRs, but had lower affinity for A2 AdoRs in guinea pig hearts and brain striatum than did either CPX or NAX. In DDT1 MF-2 cells, all three alkylxanthines had similar affinities for A1 AdoRs, whereas the affinity of N-0861 for A1 AdoRs was significantly lower. ENX appears to be the most A1 AdoR subtype-selective of the alkylxanthine class of AdoR antagonists reported to date.

AB - The objective of this study was to characterize the adenosine receptor (AdoR) antagonistic properties of a newly synthesized alkylxanthine, 1,3- dipropyl-8[2-(5,6-epoxy)norbornyl]xanthine (ENX), and compare them to those of 1,3-dipropyl-8-(cyclopentyl)xanthine (CPX), 1,3-dipropyl-8-(3- noradamantyl)xanthine (NAX) and (±)-N6-endo-norbornan-2-yl-9-methyladenine (N-0861). The potencies and selectivities of ENX, CPX, NAX and N-0861 were determined by functional studies of guinea pig isolated perfused hearts, and by radioligand binding assays for A1 and A(2a) AdoRs in the guinea pig forebrain and striatum. ENX competitively antagonized A1 AdoR-mediated prolongations of atrioventricular nodal conduction time caused by Ado or by 2-chloro-N6-cyclopentyladenosine, but not those caused by carbachol (0.14 μM) or MgCl2 (3 mM). Schild analysis of 2-chloro-N6-cyclopentyladenosine- antagonist competition curves yielded pA2 values for ENX, CPX and NAX of 8.45 ± 0.19, 8.55 ± 0.28 and 8.79 ± 0.15, respectively. ENX (30 μM) and N-0861 (30 μM) did not attenuate the A2 AdoR-mediated increase in coronary conductance caused by adenosine. CPX and NAX attenuated the coronary vasodilation caused by adenosine with IC50 values of 1.5 and 7.1 μM, respectively. Radioligand binding assays revealed that ENX, CPX and NAX and N-0861 had a 400-, 209-, 110- and 10-fold greater affinity, respectively, for A1 than for A(2a) AdoRs of guinea pig brain membranes. Thus, ENX was equipotent with CPX and NAX and more potent than N-0861 (pA2 = 6.2) as an antagonist at A1 AdoRs, but had lower affinity for A2 AdoRs in guinea pig hearts and brain striatum than did either CPX or NAX. In DDT1 MF-2 cells, all three alkylxanthines had similar affinities for A1 AdoRs, whereas the affinity of N-0861 for A1 AdoRs was significantly lower. ENX appears to be the most A1 AdoR subtype-selective of the alkylxanthine class of AdoR antagonists reported to date.

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