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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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Vittori S,Lorenzen A,Stannek C,Costanzi S,Volpini R,IJzerman AP,Kunzel JK,Cristalli G

doi

10.1021/jm9911231

keywords:

subject

Has Abstract

pub_date

2000-01-27 00:00:00

pages

250-60

issue

2

eissn

0022-2623

issn

1520-4804

pii

jm9911231

journal_volume

43

pub_type

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