Influence of the molecular structure of N6-(omega-aminoalkyl)adenosines on adenosine receptor affinity and intrinsic activity.
The affinities of a series of N6-(omega-aminoalkyl)adenosines as probes for A1 and A2 adenosine receptors were determined in various radioligand binding assays and the intrinsic activities were measured in adenylate cyclase assays. Clear species differences were noticed for A1 receptor affinity of these adenosine receptor agonists, the compounds being more active in calf than in rat brain tissue. The affinity profile within the series was, however, rather similar in both membrane preparations, with N6-9-aminononyladenosine displaying highest affinity. The A2 receptor affinities were comparable to values measured for the A1 receptor in its low affinity state, as assessed with a radiolabelled antagonist in the presence of 1 mM GTP. Calculation of the intrinsic activities of the adenosine analogues from their modulating action on adenylate cyclase showed almost all the compounds to be equally effective to (-)-N6-(R-phenylisopropyl) adenosine, on either A1 or A2 adenosine receptors. N6-3-Aminopropyl- and N6-12-aminododecyladenosine, however, proved to be partial agonists, the first on A1 and the second on A2 adenosine receptors. The data are used as the basis for a discussion of adenosine receptor subtype selectivity and intrinsic activity in general.
Dept. of Medicinal Chemistry, Center for Bio-Pharmaceutical Sciences, Leiden, The Netherlands.
I M
IM
Pirovano
A P
AP
IJzerman
P J
PJ
Van Galen
W
W
Soudijn
D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000201:enzymology; D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D015394:Molecular Structure; D011869:Radioligand Assay; D051381:Rats; D011983:Receptors, Purinergic / Q000378:metabolism*
D011983:Receptors, Purinergic; D000262:Adenylyl Cyclases; D000241:Adenosine