title: N-cycloalkyl derivatives of adenosine and 1-deazaadenosine as agonists and partial agonists of the A(1) adenosine receptor.
abstract: A number of cycloalkyl substituents (from C-3 to C-8) have been introduced on the 6-amino group of adenosine, 1-deazaadenosine, and 2'-deoxyadenosine, bearing or not a chlorine atom at the 2-position, to evaluate the influence on the A(1) and A(2A) affinity of steric hindrance and lipophilicity. Furthermore, the guanosine 5'-triphosphate (GTP) shift and the maximal induction of guanosine 5'-(gamma-thio)triphosphate ([(35)S]GTPgammaS) binding to G proteins in rat brain membranes were used to determine the intrinsic activity of these nucleosides at the A(1) adenosine receptor. All compounds of the ribose-bearing series proved to be full agonists, the 1-deaza derivatives showing affinities for the A(1) receptor about 10-fold lower than the corresponding adenosines. On the other hand, all the 2'-deoxyribose derivatives bind to the A(1) receptor with affinities in the high nanomolar range, with the 2-chloro substituted compounds showing slightly higher affinities than the 2-unsubstituted counterparts. In terms of the potencies, the most potent compounds proved to be those bearing four- and five-membered rings. Both GTP shifts and [(35)S]-GTPgammaS experiments showed that most of the 2'-deoxyadenosine derivatives are partial agonists. The 2'-deoxyadenosine derivatives which were identified as partial agonists consistently detected fewer A(1) receptors in the high-affinity state than full agonists. However, it is worthwhile noting that there was not a simple linear relationship between receptor occupancy and activation. These results indicate that a critical density of A(1) adenosine receptors in the high-affinity state is required for G protein activation.
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Camerino, 62032 Camerino, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Vittori
authors.forename: A
authors.initials: A
authors.lastname: Lorenzen
authors.forename: C
authors.initials: C
authors.lastname: Stannek
authors.forename: S
authors.initials: S
authors.lastname: Costanzi
authors.forename: R
authors.initials: R
authors.lastname: Volpini
authors.forename: A P
authors.initials: AP
authors.lastname: IJzerman
authors.forename: J K
authors.initials: JK
authors.lastname: Kunzel
authors.forename: G
authors.initials: G
authors.lastname: Cristalli
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D010627:Phenethylamines / Q000378:metabolism; D058906:Purinergic P1 Receptor Agonists; D011869:Radioligand Assay; D051381:Rats; D014372:Tubercidin / Q000737:chemistry / Q000494:pharmacology*; D014970:Xanthines / Q000378:metabolism
chemical_list: D010627:Phenethylamines; D058906:Purinergic P1 Receptor Agonists; D014970:Xanthines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C048086:1-deazaadenosine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine; D014372:Tubercidin