Adenosine partial agonists

Schaddelee MP, Collins SD, DeJongh J, de Boer AG, Ijzerman AP, Danhof M. Pharmacokinetic/pharmacodynamic modelling of the anti-hyperalgesic and antinociceptive effect of adenosine A1 receptor partial agonists in neuropathic pain. Eur J Pharmacol 2005 May 9 514(2-3) 131-40. 

Mathot RAA, van der Wenden EM, Soudijn W, Ijzerman AP, Danhof M. Deoxyribose analogues of A -cyclopcnty I adenosine (CPA) are partial agonist at the adenosine Ai receptor in vivo. Br J Pharmacol 1995 116 1957-1964. 

Roelen H, Veldman N, Spek AL, von Frijtag Drabbe Kiinzel JK, Mathot RAA, Ijzerman AP. /V6,C8-disubstitutcd adenosine derivatives as partial agonist for adenosine A receptors. J Med Chem 1996 39 1463-1471. 

Lorenzen A, Sebastiao AM, Sellink A, Vogt H, Schwabe U, Ribeiro JA, Ijzerman AP. Biological activities of /V6,C8-disubstitutcd adenosine derivatives as partial agonist at rat brain adenosine A, receptors. Eur J Pharmacol 1997 334 299-307. 

Dalpiaz A, Townsend-Nicholson A, Beukers MW, Schofield P, Ijzerman AP. Thermodynamics of full agonist, partial agonist and antagonist binding to wild type and mutant adenosine Ai receptors. Biochem Pharmacol 1998 56 1437-1445. 

Changes in the activity of adenosine receptors have been implicated in the stimulant effects of drugs like caffeine. Carbamazepine exhibits a partial agonist effect on adenosine receptors, and experimental evidence suggests that the reduced reuptake and release of noradrenaline caused by the drug are due to its interaction with these receptors. The precise relevance of these findings to its anticonvulsant and psychotropic effects is presently unclear. 

Gao Z-G, Jacobson KA (2004) Partial agonists for A3 adenosine receptors. Curr Topics Med Chem 4 855-862... 

Borea PA, Varani K, Dalpiaz A, Capuzzo A, Fabbri E, IJzerman AP (1994) Full and partial agonistic behavior and thermodynamic binding parameters of adenosine A3 receptor ligands. Eur J Pharmacol 267(1) 55-61... 

Cosyn L, Palaniappan KK, Kim SK, Duong HT, Gao ZG, Jacobson KA, Van Calenbergh S (2006b) 2-Triazole-substituted adenosines a new class of selective A3 adenosine receptor agonists, partial agonists, and antagonists. J Med Chem 49(25) 7373-7383... 

Thus N6-(3-iodobenzyl)adenosine (MRS541, structure not shown) acts as partial agonist (46% A3 efficacy) while the 2-chloro-N6-(3-iodobenzyl)adenosine (MRS542, structure not shown) behaves as potent but non selective A3 AR antagonists (K. A3 = 1.8 nM, EC50 A2B > 10,000 nM, K A2a = 197 nM, K A, = 16.8 nM) (Gao et al. 2006). It has to be remarked that the efficacy of the latter compound is completely restored by the replacement of the 4 -hydroxymethylene group with a 5 -methyluronamide function (Cl-IB-MECA). 

Triazole-substituted adenosines a new class of selective A3 adenosine receptor agonists, partial agonists, and antagonists. J Med Chem 49 7373-7383... 

The rise in heart rate (Fig. 4b) observed within the first minutes of infusion is probably best described as a reflex tachycardia. The same phenomenon has also been observed with the Aj -selective full agonist CGS 21680. The latter compound, however, reached peak values (data not shown) as high as 550 beats per minute (bpm), contrasting to the mean highest value for theophylline-7-riboside of 425 bpm. CPA in the same experimental setup caused a decrease in heart rate to as low as 150 bpm. Thus, theophylline-7-riboside behaved as a partial agonist on parameters that are strictly A, receptor mediated (heart rate) or both A and Aj (mean arterial pressure). In conclusion, theophylline-7-riboside, developed from the antagonist theophylline, may be a useful tool as a partial agonist for adenosine receptors. Its low affinity is a potential drawback, which warrants the development of other compounds for which theophylline-7-riboside may be a lead. 

The in vivo potencies (ECjo.u) of the compounds correlated well with their apparent adenosine A, receptor affinities as determined in the absence of GTP (Table 2). With respect to intrinsic activity a fair correlation between relative GTP shifts and E values was observed. The 2 - and 3 -deoxy analogues of CPA proved partial agonists in vitro and in vivo. 

Subcutaneous infusions Intranasal Sublingual Partial agonists Terguride Adenosine A23 Istradefylline (KW-6002)... 

All interactions between UFH and platelets are complex and only partially elucidated, but it is known that heparin itself stimulates platelets via a platelet-binding domain of heparin (14). In the therapeutic range, UFH induces the release of P-selectin and activates GPIIb/llla receptors when adenosine diphosphate (ADP) or thrombin receptor agonist peptide stimulates platelet responsibility, and then enhances platelet aggregation (15,16). Even in healthy individuals, agonist-induced platelet aggregation is often enhanced when heparin is added. 

More recently, studies have been performed to determine the responsiveness of rat juxtameduUary afferent arterioles to receptor-selective P2- purinoceptor agonists [246]. Experiments were performed in vitro using the blood perfused juxtameduUary nephron technique, combined with videomicroscopy. The presence of multiple P2 receptors on juxtameduUary afferent arterioles and the classification of these receptors as members of the P2X- and P2Y2 (P2U)-receptor subtypes was demonstrated. In another study, the relative contributions of adenosine A1 and A2a receptors to the responsiveness of the renal microvasculature to adenosine was investigated [247]. The presence of adenosine A1 and A2a receptors on afferent and efferent arterioles of juxtameduUary nephrons was demonstrated. Also, adenosine A2a receptor-mediated vasodilation partially buffered adenosine-induced vasoconstriction in both pre- and postglomerular segments of the renal microvasculature. 

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