title: 5'-substituted adenosine analogs as new high-affinity partial agonists for the adenosine A1 receptor.
abstract: 5'-(Alkylthio)-, 5'-(methylseleno)-, and 5'-(alkylamino)-substituted analogues of N6-cyclopen-tyladenosine (CPA) were synthesized in 30-50% overall yields. The affinities of these compounds for the adenosine A1 and A2A receptors were determined in rat brain membranes. The 5'-substituted CPA analogues proved selective for the adenosine A1 receptors, displaying affinities in the nanomolar range. The compounds were also evaluated for their ability to stimulate [35S]GTP gamma S binding, also in rat brain membranes. The Ki values in receptor binding studies corresponded well to the EC50 values thus obtained. Intrinsic activities of the compounds were tested in vitro by determining the GTP shift in receptor binding studies as well as the maximal binding of [35S]GTP gamma S. It appeared that the 5'-thio and 5'-seleno derivatives in particular behaved as partial agonists.
authors.affiliation: Div. Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.
authors.forename: E M
authors.initials: EM
authors.lastname: van der Wenden
authors.forename: M
authors.initials: M
authors.lastname: Carnielli
authors.forename: H C
authors.initials: HC
authors.lastname: Roelen
authors.forename: A
authors.initials: A
authors.lastname: Lorenzen
authors.forename: J K
authors.initials: JK
authors.lastname: von Frijtag Drabbe Künzel
authors.forename: A P
authors.initials: AP
authors.lastname: IJzerman
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007700:Kinetics; D058906:Purinergic P1 Receptor Agonists; D051381:Rats; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058906:Purinergic P1 Receptor Agonists; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C048599:N(6)-cyclopentyladenosine; D000241:Adenosine