Pharmacology of the new selective A2a adenosine receptor agonist 2-hexynyl-5'-N-ethylcarboxamidoadenosine.
The pharmacological profile of 2-hexynyl-5'-N-ethylcarboxamidoadenosine (2HE-NECA, CAS 141018-30-6), a new selective A2a adenosine receptor agonist, was characterized. In binding studies on both rat and bovine brain, 2HE-NECA was more potent on A2a receptors (Ki = 2.2 and 1.5 nmol/l, respectively) than the reference A2a agonist, 2-[4-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoaden osi ne (CPEC) or the non-selective adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA). The drug displayed a good A2a vs A1 receptor selectivity in brain tissues of both animal species (60- and 160-fold, respectively). In functional studies, 2HE-NECA showed marked vasodilating properties in rat aorta, bovine and porcine coronary arteries. The vasodilatory response in the porcine coronary preparation was greater for 2HE-NECA (EC50 = 23.3 nmol/l) than for CPEC (EC50 = 58.7 nmol/l) or NECA (EC50 = 76.6 nmol/l). In the rat Langendorff model, in which global ischemia was induced, 2HE-NECA (100 nmol/l) significantly prevented the risk of diastolic pressure and coronary perfusion pressure occurring during postischemic reperfusion. The in vitro antiaggregatory activity of 2HE-NECA (IC50 = 0.07 mumol/l), as tested in rabbit platelets, was higher than that found with NECA (IC50 = 0.2 mumol/l) or CPEC (IC50 = 2.16 mumol/l). In spontaneously beating rat atria, which are responsive to A1-receptor stimulation, 2HE-NECA did not show any negative chronotropic activity up to micromolar concentrations. In conscious spontaneously hypertensive rats, 2HE-NECA administered intraperitoneally caused a dose-dependent reduction in systolic blood pressure (ED30 = 0.005 mg/kg) with minimal reflex tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)
Monopoli
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Research Laboratories, Schering-Plough S.p.A., Comazzo, Milan, Italy.
Conti
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Zocchi
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Casati
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Volpini
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Cristalli
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Ongini
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D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000031:analogs & derivatives; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D058906:Purinergic P1 Receptor Agonists; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine
D010975:Platelet Aggregation Inhibitors; D058906:Purinergic P1 Receptor Agonists; C076864:2-hexynyladenosine-5'-N-ethylcarboxamide; D019830:Adenosine-5'-(N-ethylcarboxamide); D000241:Adenosine