title: 2,8-Disubstituted adenosine derivatives as partial agonists for the adenosine A2A receptor.
abstract: Novel 2,8-disubstituted adenosine derivatives were synthesized in good overall yields starting from 2-iodoadenosine. Binding affinities were determined for rat adenosine A(1) and A(2A) receptors and human A(3) receptors. Some compounds displayed good adenosine A(2A) receptor affinities, with most of the 2-(1-hexynyl)- and 2-[(E)-1-hexenyl]-substituted derivatives having K(i) values in the nanomolar range. Although the introduction of an 8-alkylamino substituents decreased the affinity for the adenosine A(2A) receptor somewhat, the selectivity for this receptor compared to A(3) was improved significantly. The 8-methylamino (12) and 8-propylamino (14) derivatives of 2-(1-hexynyl)adenosine (3), showed reasonable A(2A) receptor affinities with K(i) values of 115 and 82nM, respectively, and were 49- and 26-fold selective for the adenosine A(2A) receptor compared to the A(3) receptor. The compounds were also evaluated for their ability to stimulate the cAMP production in CHO cells expressing the human adenosine A(2A) receptor. 2-(1-Hexynyl)adenosine (3) and 2-[(E)-1-hexenyl]adenosine (4) both showed submaximal levels of produced cAMP, compared to the reference full agonist CGS 21680, and thus behaved as partial agonists. Most 8-alkylamino-substituted derivatives of 3, displayed similar cAMP production as 3, and behaved as partial agonists as well. Introduction of alkylamino groups at the 8-position of 4, showed a slight reduction of the efficacy compared to 4, and these compounds were partial agonists also.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, PO Box 9502, 2300 RA Leiden, The Netherlands. etilburg@rnc.vu.nl
authors.forename: Erica W
authors.initials: EW
authors.lastname: van Tilburg
authors.forename: Matty
authors.initials: M
authors.lastname: Gremmen
authors.forename: Jacobien
authors.initials: J
authors.lastname: von Frijtag Drabbe Künzel
authors.forename: Miriam
authors.initials: M
authors.lastname: de Groote
authors.forename: Ad P
authors.initials: AP
authors.lastname: IJzerman
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D001921:Brain / Q000378:metabolism; D016466:CHO Cells / Q000187:drug effects; D006224:Cricetinae; D000242:Cyclic AMP / Q000032:analysis / Q000096:biosynthesis; D006801:Humans; D008744:Methylamines / Q000737:chemistry / Q000494:pharmacology; D008956:Models, Chemical; D011437:Propylamines / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D008744:Methylamines; D011437:Propylamines; D000242:Cyclic AMP; D000241:Adenosine