The Pharmacologic Estimation of Potencies of Agonists and Antagonists in the Classification of Adenosine Receptors

Kenakin, Terry; Leighton, H J

doi:10.1007/978-1-4684-4886-3_12

Cited by 9 publications

(6 citation statements)

References 46 publications

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“…However, our data are also compatible with the existence of other receptors which have been recently characterized (Chin et al, 1985). A quantatitive analysis of the receptors mediating the electrophysiological action of adenosine, especially by the use of antagonists (Kenakin & Leighton, 1985), therefore appears necessary.…”

Section: Discussionsupporting

confidence: 86%

Adenosine inhibits epileptiform activity arising in hippocampal area CA3

Ault

Wang

1986

British J Pharmacology

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1 The ability of adenosine and structurally-related compounds to inhibit epileptiform activity induced by bicuculline in the CA3 region of the hippocampal slice of the rat was examined. 3 Theophylline (30 gM) increased the rate of bursting and antagonized the effect of exogenous adenosine. 4 Dipyridamole (0.03-1 I1M) reduced the occurrence of burst firing. 5 In slices untreated with bicuculline, theophylline (30gM) and adenosine deaminase (Ogg ml-') induced bursting activity. 6 These results demonstrate that purinoceptor agonists can suppress epileptiform activity in the hippocampus and suggest that adenosine may act as an endogenous anticonvulsant.

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Section: Discussionsupporting

confidence: 86%

Adenosine inhibits epileptiform activity arising in hippocampal area CA3

Ault

Wang

1986

British J Pharmacology

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“…The decreased sensitivity to SPD can be better understood by inclusion of an alternative transport process, and perhaps even an additional transport protein. Analogous behavior has been observed using in vitro model systems designed to study the effect of uptake blockers on cellular responses to agonists. − …”

Section: Resultsmentioning

confidence: 70%

The Effect of Polyamine Homologation on the Transport and Cytotoxicity Properties of Polyamine−(DNA-Intercalator) Conjugates

Phanstiel¹,

Price²,

Wang³

et al. 2000

J. Org. Chem.

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An efficient five-step synthetic method was developed to access a homologous series of spermidine-acridine and spermidine-anthracene conjugates. The derivatives were comprised of a spermidine fragment covalently tethered at its N4 position to either an acridine or anthracene nucleus via an aliphatic chain (e.g., spermidine-[aliphatic tether]-acridine). The distance separating the spermidine and aromatic nucleus was altered by using different tethers comprised of four or five methylene units, respectively. These ligands (2-5) were shown to inhibit human DNA topoisomerase-II (TOPO-II) activity at 10 microM. Enzymatic activity was assessed as the ability to unknot (decatenate) and cleave kinetoplast DNA (kDNA). Polyamine conjugation did not disrupt the ability of the acridine-spermidine conjugates 2 and 3 to inhibit TOPO-II activity as compared with the 9-aminoacridine and 9-(N-butyl)aminoacridine controls (at 10 microM). In general, the acridine derivatives (2 and 3) showed higher TOPO-II inhibitory activity than their anthracene counterparts (4 and 5). However, this trend was reversed in a whole cell assay with L1210 (murine leukemia) cells, wherein the anthracene analogues were more potent than their acridine counterparts. In this regard the qualitative enzyme-based assay did not predict the trends in the corresponding IC(50) values. Within either series insertion of an additional methylene unit did not significantly alter activity. While the appended spermidine unit did not disrupt TOPO II inhibition by the tethered DNA intercalator, it did provide an alternative mode of entry into the cell as demonstrated by spermidine protection assays. These results were compared with a spermine-intercalator analogue. Of all the conjugates tested the N(4)-(4-(9-aminoacridinyl)butyl)spermine hexahydrochloride (conjugate 16)resulted in the highest degree of L1210 cell rescue upon cotreatment of the cells with exogenous spermidine. It was concluded that the monoalkylated spermine motif present in 16 holds promise as a better vector than its N4 monoalkylated spermidine counterpart.

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“…Adenosine was not utilized in these studies because of the complicating effects of metabolic uptake and degradation processes for this purine known to be present in tissues (i.e. Kenakin & Leighton, 1985) including the kidney (Trimble & Coulson, 1984). Initial studies indicated that 2-chloroadenosine and L-PIA produced a modest vasodilatation.…”

Section: Discussionmentioning

confidence: 99%

“…The antagonism of vasoconstriction by PACPX and the relative order of potency of the agonists as vasoconstrictor agents were consistent with the hypothesis that this was a A1-receptor-mediated effect. Unfortunately, the biphasic nature of the dose-response curves made proper receptor classification by Schild analysis or quantitation of potency-ratios (Kenakin & Leighton, 1985) impossible.…”

Section: Discussionmentioning

confidence: 99%

An in vitro analysis of purine‐mediated renal vasoconstriction in rat isolated kidney

Kenakin

Pike

1987

British J Pharmacology

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1 In the rat isolated perfused kidney, 2-chloroadenosine and L-N6-phenyl-isopropyl adenosine (L-PIA) produced a modest vasodilatation. 2 After kidneys had been pretreated with methoxamine (to elevate vascular tone) and forskolin (to activate adenyl cyclase and reduce vascular tone), both purine agonists produced vasoconstriction at low doses and vasodilatation at higher doses. This was consistent with the working hypothesis that vasoconstriction resulted from activation ofA1-purinoceptors mediating adenyl cyclase inhibition and vasodilatation from activation of A2-purinoceptors stimulating adenyl cyclase. 3 These kidney preparations also demonstrated a marked potentiation of purine-mediated vasoconstriction in the presence of various concentrations of 8-p-sulpho-phenyltheophylline (8-SPT), a drug reported in the literature to be a competitive antagonist of Al-and A2-purinoceptors.4 Maximal renal vasoconstriction to 2-chloroadenosine and L-PIA was observed in the presence of 10 mM 8-SPT; the fact that this vasoconstriction was sensitive to the selective A,-receptor antagonist 8-(2-amino-4-chlorophenyl)-1,3-dipropylxanthine (PACPX) and that the order of potency of agonists for this effect was L-PIA > 2-chloroadenosine > D-PIA > N6-ethylcarboxamide adenosine (NECA) was consistent with activation of vascular A,-purinoceptors.5 While these data are consistent with the hypothesis that purines activate vascular Al-and A2-receptors in the rat isolated kidney, the nature of the results did not allow definitive classification of the receptors mediating the purine effects.

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The Pharmacologic Estimation of Potencies of Agonists and Antagonists in the Classification of Adenosine Receptors

Cited by 9 publications

References 46 publications

Adenosine inhibits epileptiform activity arising in hippocampal area CA3

Adenosine inhibits epileptiform activity arising in hippocampal area CA3

The Effect of Polyamine Homologation on the Transport and Cytotoxicity Properties of Polyamine−(DNA-Intercalator) Conjugates

An in vitro analysis of purine‐mediated renal vasoconstriction in rat isolated kidney

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