Separation of vasodilator and negative chronotropic actions in analogues of adenosine

Einstein, Rosemarie; Angus, James A.; Cobbin, L. B.; Maguire, M. Helen

doi:10.1016/0014-2999(72)90016-7

Cited by 20 publications

(7 citation statements)

References 6 publications

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“…Like several purines, such as I-methylisoguanosine (Davies et al, 1980a), CBZ is a moderately potent inhibitor of benzodiazepine binding, and its anticonvulsant activity against pentylenetetrazole-induced seizures in mice can be partially blocked by the benzodiazepine antagonist Ro15-1788 . While the existence of separate Al receptors (labelled by PIA) and A2 receptors (labelled by NECA) has been suggested, largely as a result of the differing effects of these agents on adenylate cyclase and thus on subsequent control of metabolic events (Van Calker et al, 1979;Londos et a]., 1980), other studies, such as those of the cardiovascular actions of adenosine analogues, have also suggested the presence of adenosine receptor subclasses (Einstein et al, 1972). A comparison of the inhibition of the binding of [3H]PlA and [3H]NECA to whole rat brain membranes by a series of purines and methylxanthines has not been previously described.…”

Section: Discussionmentioning

confidence: 99%

Interactions of the Anticonvulsant Carbamazepine with Adenosine Receptors. 1. Neurochemical Studies

1983

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At therapeutic concentrations the tricyclic anticonvulsant carbamazepine inhibited the binding of the adenosine analogue [3H]L-N6-phenylisopropyladenosine ([3H]PIA) to rat brain membranes (Ki = 46 microM) in vitro. Carbamazepine interacted much less potently with muscarinic cholinergic, beta-adrenergic, gamma-aminobutyric acid, or L-glutamate binding sites. Carbamazepine was of lower potency (Ki = 112 microM) as an inhibitor of the binding of the putative A2 adenosine agonist [3H]5'-N-ethylcarboxamidoadenosine. GTP greatly reduced the potencies of purine agonists, but not antagonists, as inhibitors of [3H]PIA. The potency of carbamazepine, like that of the antagonist theophylline, was not reduced by GTP. Studies on the adenosine-stimulated adenylate cyclase activity in guinea pig brain slices also revealed theophyllinelike activity of carbamazepine. The possible relevance of agonist and antagonist interactions with adenosine receptors to the anticonvulsant action of carbamazepine is discussed.

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Section: Discussionmentioning

confidence: 99%

Interactions of the Anticonvulsant Carbamazepine with Adenosine Receptors. 1. Neurochemical Studies

1983

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“…This proposal is based on the opposite effects of 2-methylthioadenosine and 2-fluoroadenosine, presumably because of the conformational differences, on heart rate and blood pressure. In addition to these intrinsically different conformational effects, the steric effect of a 2-methylthio substituent postulated to preclude a specific binding to a cardiac receptor (37) It is apparent from the glycosidic conformational energy profiles of the molecules presented here and of others discussed that the nature of the purine base has a significant effect on glycosidic conformation. These conformational preferences are retained and expressed (but are not necessarily dominant) in any environment such as single-stranded or duplex polynucleotide structures, and they appear to affect the overall conformation of the polynucleotides based on the experimental determination of their interferon or virus-inhibiting character, which is apparently conformationally controlled.…”

Section: Resultsmentioning

confidence: 93%

Interferon induction: a conformational hypothesis.

Miles¹,

Miles²,

Eyring³

1979

Proc. Natl. Acad. Sci. U.S.A.

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The ability of polynucleotides or polynucleotide duplexes such as poly (I).poly(C) to induce interferon production is proposed to depend on the existence of certain stable glycosidic orientations. It appears that a slight increase in instability of 1-3 kcal/mole (1 cal = 4.184 J) in the conformational regions near 200, 800, and 1600 leads to a loss of potency with respect to interferon induction. Thus, it is proposed that, for a lynucleotide to exist in the overall conformation necessary for interferon induction, stability of glycosidic orientations near 200, 800, and 1600 may be necessary to confer flexibility and activity on polynucleotide structures. This proposed conformational triad of stable conformational regions essential to interferon induction is based on the results of conformational energy calculations of the glycosidic rotational profiles of adenosine, 7-deazaadenosine, inosine, and 7-deazainosine, as well as the conformational properties of other purine nucleoside analogs, and on inferences derived from calculations about the conformational effect in polynucleotides of removing the 2'-OH group.

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“…The 2-chloro and 2-f luoro adenosines decrease both blood pressure and heart rate whereas 2-thioalkyl analogs of adenosine decrease blood pressure but increase the heart rate of anesthetized dogs (42). The cardiotoxicity of analogs of adenosine that is attributable to their resistance to deamination or phosphorylation may be avoided by structural changes that destabilize the high anti conformation.…”

Section: Discussionmentioning

confidence: 99%

“…The reason for the separation of vasodilatory and negative chronotropic actions of adenosine analogs is not known but it may have a conformational basis. Interactions between adenosine analogs having bulky substituents at the 2 position of the adenine base and the adenosine receptor site may disallow the high anti conformation at the postulated cardiac receptor (42) but still allow the high anti conformation at the postulated vascular smooth muscle receptor (42).…”

Section: Discussionmentioning

confidence: 99%

Conformational basis for the activation of adenylate cyclase by adenosine

Miles

Eyring

1977

Proc. Natl. Acad. Sci. U.S.A.

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The ability of adenosine to stimulate adenylate cyclase IATP pyrophosphate-lyase (cyclizing), EC 4.6.1.11 and increase adenosine 3':5'-cyclic monophosphate (cAMP) levels has important biochemical consequences. These include the suppression of immune responses and cardiovascular effects. Recent investigations involving the ability of adenosine and adenosine analogs to stimulate adenylate cyclase provided experimental data that appear to be correlated with the ability of adenosine and analogs of adenosine to exist in the glycosidic high anti conformation. There are several aspects to the toxicity associated with an excess of adenosine (1-11). The enzymes adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4) and adenosine kinase (ATP:adenosine-5'-phosphotransferase, EC 2.7.1.20) compete for adenosine. At higher concentrations of adenosine, adenosine deaminase dominates (11)(12)(13)(14) and protects the body from the effects of an excess of adenosine. One of these effects is the suppression of immune responses associated with the activation by adenosine of adenylate cyclase ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.11 which increases cAMP levels (15, 16). Adenosine stimulation of adenosine 3':5'-cyclic monophosphate (cAMP) production is attributed to the interaction of adenosine with a receptor for adenosine on the external cell surface (15,(17)(18)(19)(20)(21)(22)(23)(24). Immunodeficiency diseases have been associated with the loss of adenosine deaminase activity (5, 25-32).The coronary vasodilator activity of adenosine has recently been reviewed (33,34). The cardiovascular effects of adenosine are potentiated by inhibitors of either adenosine deaminase or the uptake of adenosine by the heart (35-42), both of which increase extracellular adenosine concentrations which stimulates adenylate cyclase.Factors, such as the loss of adenosine deaminase activity, that increase adenosine levels result in increased cAMP levels which are responsible for the immunosuppressive (5, 15) and cardiovascular (33-42) effects of adenosine. In both situations the action of adenosine at a receptor on the external cell surface (15, 17-24) appears to require that adenosine be oriented in the glvcosidic high anti conformation. This conclusion is suggested by the correlation between the conformational properties of adenosine and adenosine analogs and their capacities to stimulate adenylate cyclase. CALCULATIONS In order to calculate the conformational differences among adenosine, 2'-deoxyadenosine, and 9-1-D-arabinofuranosyladenine (Ara-adenine) we used the iterative extended Huckel theory (IEHT) method (43). The starting coordinates for the calculations were taken from the crystal structures of these molecules (44-46). The conformational definitions that we will use are shown in Fig. 1. The high anti conformation corresponds to dihedral angles between 750 and 1650. Fig. 2 shows the variation in total energy of adenosine with rotation about the glycosidic (C1'-N9) bond. The entire high anti conformation range is energetical...

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Separation of vasodilator and negative chronotropic actions in analogues of adenosine

Cited by 20 publications

References 6 publications

Interactions of the Anticonvulsant Carbamazepine with Adenosine Receptors. 1. Neurochemical Studies

Interactions of the Anticonvulsant Carbamazepine with Adenosine Receptors. 1. Neurochemical Studies

Interferon induction: a conformational hypothesis.

Conformational basis for the activation of adenylate cyclase by adenosine

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