Dog coronary artery adenosine receptor: structure of the N6-alkyl subregion

Kusachi, Shozo; Thompson, Robert D.; Bugni, William J.; Yamada, Nobuyuki; Olsson, Ray A.

doi:10.1021/jm00149a016

Cited by 46 publications

(26 citation statements)

References 5 publications

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“…Consequently, the search for new adenosine derivatives as ligands for the Al-receptor has been focussed mainly on the N 6 region. A general model for this region was introduced by Kusachi et al [4].…”

Section: Introductionmentioning

confidence: 99%

Adenosine derivatives with N⁶‐alkyl, ‐alkylamine or ‐alkyladenosine substituents as probes for the A₁‐receptor

Galen¹,

IJzerman²,

Soudijn³

1987

FEBS Letters

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Three series of Nr-substituted adenosine derivatives were synthesized, having in common an unbranched alkyl chain with lengths varying from 2 to 12 methylene units, but differing in their a~-alkyl substituents: Nr-n-alkyladenosines (I), Nr-co-amino-alkyladenosines (II) and ct og,di-(adenosin-Nr-yl)alkanes (III). The compounds of the latter series combine two functional groups in one molecule. Al-receptor affinity of these compounds was measured as inhibition of [3H]PIA binding to calf brain membranes. With relatively short chain lengths, compounds in series I are the most potent. In this series, optimum acitivity is reached with Nr-n-pentyladenosine (Ki = 0.50 nM). With short chain lengths, compounds in series II and III are 6-20-fold less potent than their congeners in series I. The potency order however is reversed with higher chain lengths. While affinity in series II and III increases strongly, reaching an optimum with the nonyl derivatives, affinity in series I decreases sharply with alkyl chains larger than 8 methylene units. Highest affinity is found with 9-amino-nonyladenosine (Ki=0.32 nM). In general, the to-aminoalkyl derivatives are somewhat more potent than the corresponding di-adenosinyl derivatives. Implications for the possible topography of the N 6 region of the A~-receptor and the area further removed from N 6 are dicussed.

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Section: Introductionmentioning

confidence: 99%

Adenosine derivatives with N⁶‐alkyl, ‐alkylamine or ‐alkyladenosine substituents as probes for the A₁‐receptor

Galen¹,

IJzerman²,

Soudijn³

1987

FEBS Letters

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“…Thus, adeno sine derivatives with non-vasoselective prop erties developed so far were not suitable for use as antihypertensive drugs. In attempts to develop vasoselective or A2 selective adeno sine derivatives, chemical modifications of adenosine in the N6, 2 or 5'-position have already been documented (10)(11)(12). However, the clinical evaluation of their therapeutic potential has not been established.…”

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confidence: 99%

Pharmacological Profile of the 2-Alkynyladenosine Derivative 2-Octynyladenosine (YT-146) in the Cardiovascular System

Kogi

Uchibori

Aihara

et al. 1991

Japanese Journal of Pharmacology

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ABSTRACT-We investigated the cardiovascular effects of 2-octynyladenosine (YT 146), an adenosine A2 agonist, in various mammalian preparations in comparison with adenosine and 2-chloroadenosine. YT-146, when intravenously administered, caused a dose-dependent decrease of blood pressure in anesthetized normotensive rats (with ED30 values of 0.4,ug/kg), and YT-146 was 250 times more potent than adenosine. Whereas adenosine and 2-chloroadenosine decreased heart rate at approximately equihypotensive doses, YT-146 had no negative chronotropic effects at hypotensive doses. Orally given YT-146 (0.1-1 mg/kg) produced a potent and long-lasting anti hypertensive effect in spontaneously hypertensive rats. YT-146 was 15.9 and 12.5 times more potent than adenosine in producing relaxation of isolated porcine coronary arteries and in increasing dog coronary blood flow, respectively. Although YT-146 was equipotent to adenosine in causing a negative inotropic effect in isolated guinea pig atria, it was less potent than adenosine in producing atrioventricular conduction block in guinea pigs. On the other hand, 2-chloroadenosine was 9.1, 1.8 and 2.4 times more potent than adenosine in lowering blood pressure, relaxing isolated porcine coronary arteries and increasing dog coronary blood flow, respectively. 2-Chloroadeno sine was the most potent in producing cardiodepression, i.e., negative inotropy and atrioventricular conduction block in guinea pigs. From these results, we concluded that YT-146 is a potent coronary vasodilator and also a potent, orally active and long acting hypotensive agent having less cardiac depressant activity. Adenosine receptors mediate a great variety of biological responses in non-excitable and excitable tissues (1). Two subtypes of adeno sine receptors have been identified, i.e., A, and A2 adenosine receptors, which mediate in hibition and stimulation of adenylate cyclase, respectively (2, 3). In the cardiovascular sys tem, it has been established that the hypoten sive action of adenosine occurs via two differ ent mechanisms, i.e., A2 receptor-mediated vasodilation (4-6) and A, receptor-mediated cardiac depression (7-9). Adenosine deriva tives synthesized so far retain the two mecha nisms of action of adenosine. The cardiode pressant action is by no means acceptable in the treatment of hypertension. Thus, adeno sine derivatives with non-vasoselective prop erties developed so far were not suitable for use as antihypertensive drugs. In attempts to develop vasoselective or A2 selective adeno

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“…This study shows that the coronary artery A 2 -adenosine receptor recognizes adenosines having N 6 substituents a great deal larger than those examined hitherto (6). Although an N 6 -phenyl substituent nearly doubles the coronary vasoactivity of adenosine (11), the still higher activity of analogues 9 and 11-19, whose MPRs range between 3 and 10, show that bulky substituents distal to the N 6 -phenyl moiety also contribute to activity, in some instances remarkably so.…”

Section: Resultsmentioning

confidence: 67%

“…Previous reports describe in detail the assay of coronary vasoactivitv in the anesthetized, open-chest dog (6,7). Such an assay estimates an EC-50, the concentration of analogue which produces a half maximum change in coronary conductance (reciprocal resistance).…”

Section: Methodsmentioning

confidence: 99%

N6-Functionalized congeners of adenosine with high potency at A2-adenosine receptors: Potential ligands for affinity chromatography

Yamada

Kirk

Daly

et al. 1986

Biochemical and Biophysical Research Communications

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SUMMARYAdenosine analogues substituted at N 6 with spacer arms designed for attachment to soluble macromolecules or to solid supports for affinity chromatography are agonists at the A 2 -adenosine receptor that mediates coronary vasodilation in the dog. The most active analogues had spacer arms terminating in −NH 2 , −NHCH 3 or in a biotin residue. Comparisons of coronary vasoactivity with affinity" for brain A 1 adenosine receptors identified one biotin-containing analogue as relatively selective for coronary A 2 receptors. The complex of this analogue with avidin retained coronary vasoactivity.Two classes of receptors, linked to adenylate cyclase, mediate many of the biological actions of adenosine: Activation of A 1 receptors inhibits the enzyme while activation of A 2 receptors stimulates the enzyme. The ligand binding peptide of the brain A 1 receptor has been identified by photoaffinity radiolabelling (1,2), but as yet neither receptor has been isolated. As a first step toward the purification of these receptors, we have applied the "functionalized congener" approach to the design of adenosine receptor ligands suitable for affinity chromatography. The essential feature of this approach is the regioselective incorporation of a spacer chain on the pharmacophore, followed by incorporation of various moieties through a terminal carboxylic acid or amine on the spacer chain. The chain consists of an N 6 substituent on the adenosine molecule or a C-8 substituent on a derivatized xanthine molecule (3,4). The binding of such analogues to rat brain A 1 receptors can be influenced by both the nature of the spacer arm and by the nature of the distal moiety.The present study extends the functionalized congener approach to the A2-adenosine receptor. We have used in vivo stimulation of coronary vasodilation (5) to measure potency of several analogues at the A 2 receptor. The comparison of this assay with previous

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Dog coronary artery adenosine receptor: structure of the N6-alkyl subregion

Cited by 46 publications

References 5 publications

Adenosine derivatives with N⁶‐alkyl, ‐alkylamine or ‐alkyladenosine substituents as probes for the A₁‐receptor

Adenosine derivatives with N⁶‐alkyl, ‐alkylamine or ‐alkyladenosine substituents as probes for the A₁‐receptor

Pharmacological Profile of the 2-Alkynyladenosine Derivative 2-Octynyladenosine (YT-146) in the Cardiovascular System

N6-Functionalized congeners of adenosine with high potency at A2-adenosine receptors: Potential ligands for affinity chromatography

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Dog coronary artery adenosine receptor: structure of the N6-alkyl subregion

Cited by 46 publications

References 5 publications

Adenosine derivatives with N6‐alkyl, ‐alkylamine or ‐alkyladenosine substituents as probes for the A1‐receptor

Adenosine derivatives with N6‐alkyl, ‐alkylamine or ‐alkyladenosine substituents as probes for the A1‐receptor

Pharmacological Profile of the 2-Alkynyladenosine Derivative 2-Octynyladenosine (YT-146) in the Cardiovascular System

N6-Functionalized congeners of adenosine with high potency at A2-adenosine receptors: Potential ligands for affinity chromatography

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Product

Resources

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Adenosine derivatives with N⁶‐alkyl, ‐alkylamine or ‐alkyladenosine substituents as probes for the A₁‐receptor

Adenosine derivatives with N⁶‐alkyl, ‐alkylamine or ‐alkyladenosine substituents as probes for the A₁‐receptor