title: Novel short-acting A2A adenosine receptor agonists for coronary vasodilation: inverse relationship between affinity and duration of action of A2A agonists.
abstract: Several potent and selective A2A adenosine receptor agonists are currently available. These compounds have a high affinity for the A2A receptor and a long duration of action. However, in situations where a short duration of action is desired, currently available A2A receptor agonists are less than ideal. From a series of recently synthesized A2A receptor agonists, two agonists (CVT-3146 and CVT-3033) with low affinity were selected for further characterization as selective and short-acting coronary vasodilators. Both compounds were selective for the A2A adenosine receptor (AdoR) versus the A1, A2B, and A3AdoR in binding and functional studies. CVT-3146 and CVT-3033 appeared to be weak partial agonists to cause cAMP accumulation in PC12 cells, but were full and potent agonists to cause coronary vasodilation, a response that has a very large A2A receptor reserve. However, the durations of action of CVT-3146 and CVT-3033 were remarkably shorter than those of the high-affinity agonists CGS21680 or WRC0470, presumably due to the relative lower affinity of CVT-3146 and CVT-3033 for the A2A receptor. Indeed, an inverse relationship was found between the affinity of the various agonists for the A2A receptor and the duration of their actions. These data indicate that low-affinity agonists can produce a response that is of equivalent magnitude but more rapid in termination than that caused by a high-affinity agonist. Hence, the low-affinity A2A agonists CVT-3146 and CVT-3033 may prove to be superior to currently available high-affinity agonists as coronary vasodilators during myocardial imaging with radionuclide agents.
authors.affiliation: Department of Pharmacological Sciences, CV Therapeutics, Palo Alto, California 94304, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Gao
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.forename: S P
authors.initials: SP
authors.lastname: Baker
authors.forename: R D
authors.initials: RD
authors.lastname: Lasley
authors.forename: S
authors.initials: S
authors.lastname: Meyer
authors.forename: E
authors.initials: E
authors.lastname: Elzein
authors.forename: V
authors.initials: V
authors.lastname: Palle
authors.forename: J A
authors.initials: JA
authors.lastname: Zablocki
authors.forename: B
authors.initials: B
authors.lastname: Blackburn
authors.forename: L
authors.initials: L
authors.lastname: Belardinelli
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D003342:Corpus Striatum / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D016716:PC12 Cells; D010627:Phenethylamines / Q000378:metabolism / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D011687:Purines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000502:physiology; D013552:Swine; D014227:Triazines / Q000378:metabolism; D014230:Triazoles / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; C430917:CVT 3033; D010627:Phenethylamines; D058906:Purinergic P1 Receptor Agonists; D011687:Purines; D011720:Pyrazoles; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D014227:Triazines; D014230:Triazoles; D014665:Vasodilator Agents; C097270:ZM 241385; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C430916:regadenoson; D000242:Cyclic AMP; D000241:Adenosine; C101949:binodenoson