General pharmacology of SDZ WAG 994, a potent selective and orally active adenosine A<sub>1</sub> receptor agonist

Wagner, H.; M, Milavec-Krizman; Gadient, F.; Menninger, Klaus; Schoeffter, Philippe; Tapparelli, Carlo; Pfannkuche, Hans-Juergen; Fozard, John R.

doi:10.1002/ddr.430340305

Cited by 23 publications

(15 citation statements)

References 34 publications

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“…Consistent with the potent antilipolytic effects in vitro, intravenously administered AMP 579 caused marked, dose-dependent reductions in plasma FFA. This is in agreement with numerous reports in the literature, where adenosine agonists have been shown to lower FFA levels in vivo in the rat (Hoffman et al, 1986;Reaven et al, 1988;Strong et al, 1993;Gardner et al, 1994;Wagner et al, 1995), dog (Wagner et al, 1995), primate (Wagner et al, 1995), and human (Schaumann and Kutscha, 1972;Quabbe et al, 1983). In addition to suppression of lipolysis, AMP 579 caused dose-related reductions in heart rate and blood pressure in the conscious rats.…”

Section: Discussionsupporting

confidence: 92%

Pharmacological characterization of AMP 579, a novel adenosine A1/A2 receptor agonist and cardioprotective

Merkel¹,

Rojas²,

Jarvis³

et al. 1998

Drug Dev. Res.

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Section: Discussionsupporting

confidence: 92%

Pharmacological characterization of AMP 579, a novel adenosine A1/A2 receptor agonist and cardioprotective

Merkel¹,

Rojas²,

Jarvis³

et al. 1998

Drug Dev. Res.

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“…CVT-2759 is a partial agonist of the A 1 AR, which in guinea pig heart seems to be useful in slowing down AV nodal conduction and thereby ventricular rate without causing AV block, bradycardia, atrial arrhythmias or vasodilation 63 . SDZ WAG 994 was extensively characterized in clinically relevant models 67 and has been in Phase I clinical trials for the potential treatment of PSVT. However, development of this agent was discontinued in 1999.…”

Section: Ars As Targets In Cardiovascular Diseasementioning

confidence: 99%

Adenosine receptors as therapeutic targets

Jacobson

Gao

2006

Nat Rev Drug Discov

1,270

1,361

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Adenosine receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischaemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chemistry research, a considerable number of selective agonists and antagonists of adenosine receptors have been discovered, and some have been clinically evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of adenosine receptor modulators considerably closer.

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“…Adenosine receptor agonists 1,2 are being studied for their potential use as antiarrhythmic, 3 antinociceptive, 4 and antilipolytic 5,6 agents (A 1 subtype); as cerebroprotective 7 and cardioprotective 8 agents (A 1 and A 3 subtypes); and as hypotensive 9 and antipsychotic 10 agents (A 2A subtype).…”

Section: Introductionmentioning

confidence: 99%

“…N 6 -cyclopentyl) at A 3 receptors are often intermediate between their respective A 1 and A 2A affinities. 1 Structurally, few ribose modifications, other than amide substitution at the 5′-position, are tolerated in adenosine agonists.…”

mentioning

confidence: 99%

Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

et al. 2000

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Adenosine receptor agonists have cardioprotective, cerebroprotective, and antiinflammatory properties. We report that a carbocyclic modification of the ribose moiety incorporating ring constraints is a general approach for the design of A 1 and A 3 receptor agonists having favorable pharmacodynamic properties. While simple carbocyclic substitution of adenosine agonists greatly diminishes potency, methanocarba-adenosine analogues have now defined the role of sugar puckering in stabilizing the active adenosine receptor-bound conformation and thereby have allowed identification of a favored isomer. In such analogues a fused cyclopropane moiety constrains the pseudosugar ring of the nucleoside to either a Northern (N) or Southern (S) conformation, as defined in the pseudorotational cycle. In binding assays at A 1 , A 2A , and A 3 receptors, (N)-methanocarba-adenosine was of higher affinity than the (S)-analogue, particularly at the human A 3 receptor (N/S affinity ratio of 150). (N)-Methanocarba analogues of various N 6 -substituted adenosine derivatives, including cyclopentyl and 3-iodobenzyl, in which the parent compounds are potent agonists at either A 1 or A 3 receptors, respectively, were synthesized. The N 6 -cyclopentyl derivatives were A 1 receptor-selective and maintained high efficacy at recombinant human but not rat brain A 1 receptors, as indicated by stimulation of binding of [ 35 S]GTP-γ-S. The (N)-methanocarba-N 6 -(3-iodobenzyl)adenosine and its 2-chloro derivative had K i values of 4.1 and 2.2 nM at A 3 receptors, respectively, and were highly selective partial agonists. Partial agonism combined with high functional potency at A 3 receptors (EC 50 < 1 nM) may produce tissue selectivity. In conclusion, as for P2Y 1 receptors, at least three adenosine receptors favor the ribose (N)-conformation.In work designed to develop potent and selective agents, the structure-activity relationships of adenosine derivatives as ligands (principally agonists) at the four subtypes of adenosine receptors (A 1 , A 2A , A 2B , and A 3 ) have been explored extensively. Adenosine receptor agonists 1,2 are being studied for their potential use as antiarrhythmic, 3 antinociceptive, 4 and antilipolytic 5,6 agents (A 1 subtype); as cerebroprotective 7 and cardioprotective 8 agents (A 1 and A 3 subtypes); and as hypotensive 9 and antipsychotic 10 agents (A 2A subtype).* Address correspondence to Dr. Kenneth A. Jacobson, Chief, Molecular Recognition Section, Bldg. 8A, Rm. B1A-19, NIH, NIDDK, LBC, Bethesda, MD 20892-0810. Tel: (301) In general, for adenosine agonists, numerous modifications of the N 6 -position with cycloalkyl and other hydrophobic moieties provide selectivity for A 1 receptors, although the affinities of these N 6 -substituted adenosine derivatives (e.g. N 6 -cyclopentyl) at A 3 receptors are often intermediate between their respective A 1 and A 2A affinities. 1 Structurally, few ribose modifications, other than amide substitution at the 5′-position, are tolerated in adenosine agonists. An intact f...

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General pharmacology of SDZ WAG 994, a potent selective and orally active adenosine A₁ receptor agonist

Cited by 23 publications

References 34 publications

Pharmacological characterization of AMP 579, a novel adenosine A1/A2 receptor agonist and cardioprotective

Pharmacological characterization of AMP 579, a novel adenosine A1/A2 receptor agonist and cardioprotective

Adenosine receptors as therapeutic targets

Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

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General pharmacology of SDZ WAG 994, a potent selective and orally active adenosine A1 receptor agonist

Cited by 23 publications

References 34 publications

Pharmacological characterization of AMP 579, a novel adenosine A1/A2 receptor agonist and cardioprotective

Pharmacological characterization of AMP 579, a novel adenosine A1/A2 receptor agonist and cardioprotective

Adenosine receptors as therapeutic targets

Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

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General pharmacology of SDZ WAG 994, a potent selective and orally active adenosine A₁ receptor agonist