5 '-substituted adenosine analogs as new high-affinity partial agonists for the adenosine A(1) receptor

5'-(Alkylthio)-, 5'-(methylseleno)-, and 5'-(alkylamino)-substituted analogues of N-6-cyclopentyladenosine (CPA) were synthesized in 30-50% overall yields. The affinities of these compounds for the adenosine A(1) and A(2A) receptors were determined in rat brain membranes. The 5'-...

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Published inJournal of medicinal chemistry Vol. 41; no. 1; pp. 102 - 108
Main Authors van der Wenden, EM, Carnielli, M, Roelen, HCPF, Lorenzen, A, von Frijtag, JK, Kunzel, D, IJzerman, AP
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 01.01.1998
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
NUCLEOSIDES
IN-VIVO
THEOPHYLLINE-7-RIBOSIDE
BRAIN MEMBRANES
RAT-BRAIN
POTENTIAL PARTIAL AGONISTS
BINDING
DERIVATIVES
N-6-CYCLOPENTYLADENOSINE
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Summary:5'-(Alkylthio)-, 5'-(methylseleno)-, and 5'-(alkylamino)-substituted analogues of N-6-cyclopentyladenosine (CPA) were synthesized in 30-50% overall yields. The affinities of these compounds for the adenosine A(1) and A(2A) receptors were determined in rat brain membranes. The 5'-substituted CPA analogues proved selective for the adenosine A(1) receptors, displaying affinities in the nanomolar range. The compounds were also evaluated for their ability to stimulate [S-35]GTP gamma S binding, also in rat brain membranes. The K-i 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 [S-35]GTP gamma S. It appeared that the 5'-thio and 5'-seleno derivatives in particular behaved as partial agonists.
ISSN:0022-2623
DOI:10.1021/jm970508l