Improving potency, selectivity, and water solubility of adenosine
A1 receptor antagonists: xanthines modified at position 3 and related
pyrimido1,2,3-cdpurinediones
S. Weyler, F. Fulle, M. Diekmann, B. Schumacher, S. Hinz, K. Klotz, and C. Muller. ChemMedChem, 1 (8):
891-902(August 2006)Weyler, Stefanie Fulle, Friederike Diekmann, Martina Schumacher,
Britta Hinz, Sonja Klotz, Karl-Norbert Muller, Christa E Research
Support, Non-U.S. Gov't Germany ChemMedChem ChemMedChem. 2006 Aug;1(8):891-902..
Abstract
The structure-activity relationships of xanthine derivatives related
to the adenosine A(1) receptor antagonists 8-cyclopentyl-1,3-dipropylxanthine
(DPCPX) and 1,3-dipropyl-8-(3-noradamantyl)xanthine (KW3902) were
investigated by focusing on variations of the 3-substituent. Aromatic
residues were well tolerated by the A(1) receptor in that position.
A moderate effect of stereochemistry was found for the 3-(1-phenylethyl)-substituted
analogue of DPCPX (S>R) at A(1) and A(3) receptors, whereas the opposite
stereoselectivity was observed at the A(2) receptor subtypes. A 3-hydroxypropyl
substituent was found to be optimal for high A(1) affinity and selectivity.
The most potent compound of the present series was 1-butyl-3-(3-hydroxypropyl)-8-(3-noradamantyl)xanthine
(10 c), which exhibits a K(i) value of 0.124 nM at rat, and 0.7 nM
at human adenosine A(1) receptors, combined with high selectivity
(>>200-fold) versus the other receptor subtypes. The similarly potent
8-cyclopentyl-3-(3-hydroxypropyl)-1-propylxanthine was converted
into a water-soluble phosphate prodrug, which may become a useful
pharmacological tool for in vivo studies. 8-Alkyl-2-(3-noradamantyl)pyrimido1,2,3-cdpurine-8,10-diones,
which can be envisaged as xanthine analogues with a fixed 3-propyl
substituent, were identified as a new class of potent, selective
adenosine A(1) receptor antagonists. For example, compound 14 (8-butyl-substituted)
exhibits a K(i) value of 13.8 nM at human A(1) receptors. A selection
of the most potent compounds was investigated in (35)SGTPgammaS
binding assays and showed inverse agonistic activity. Their efficacy
was generally lower than that of the full inverse agonist DPCPX,
and depended on subtle structural changes. Some of the new compounds
belong to the most potent and selective A(1) antagonists described
to date.
Improving potency, selectivity, and water solubility of adenosine
A1 receptor antagonists: xanthines modified at position 3 and related
pyrimido1,2,3-cdpurinediones
%0 Journal Article
%1 Weyler2006
%A Weyler, S.
%A Fulle, F.
%A Diekmann, M.
%A Schumacher, B.
%A Hinz, S.
%A Klotz, K. N.
%A Muller, C. E.
%D 2006
%J ChemMedChem
%K & A1/*antagonists Adamantane/*analogs Adenosine Animals Cultured Humans Phosphates/chemistry Prodrugs/chemistry/*pharmacology Rats Relationship Solubility Structure-Activity Water/chemistry Xanthine/*chemistry Xanthines/chemistry/*pharmacology derivatives/chemistry/pharmacology inhibitors Receptor Cell
%N 8
%P 891-902
%T Improving potency, selectivity, and water solubility of adenosine
A1 receptor antagonists: xanthines modified at position 3 and related
pyrimido1,2,3-cdpurinediones
%U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16902942
%V 1
%X The structure-activity relationships of xanthine derivatives related
to the adenosine A(1) receptor antagonists 8-cyclopentyl-1,3-dipropylxanthine
(DPCPX) and 1,3-dipropyl-8-(3-noradamantyl)xanthine (KW3902) were
investigated by focusing on variations of the 3-substituent. Aromatic
residues were well tolerated by the A(1) receptor in that position.
A moderate effect of stereochemistry was found for the 3-(1-phenylethyl)-substituted
analogue of DPCPX (S>R) at A(1) and A(3) receptors, whereas the opposite
stereoselectivity was observed at the A(2) receptor subtypes. A 3-hydroxypropyl
substituent was found to be optimal for high A(1) affinity and selectivity.
The most potent compound of the present series was 1-butyl-3-(3-hydroxypropyl)-8-(3-noradamantyl)xanthine
(10 c), which exhibits a K(i) value of 0.124 nM at rat, and 0.7 nM
at human adenosine A(1) receptors, combined with high selectivity
(>>200-fold) versus the other receptor subtypes. The similarly potent
8-cyclopentyl-3-(3-hydroxypropyl)-1-propylxanthine was converted
into a water-soluble phosphate prodrug, which may become a useful
pharmacological tool for in vivo studies. 8-Alkyl-2-(3-noradamantyl)pyrimido1,2,3-cdpurine-8,10-diones,
which can be envisaged as xanthine analogues with a fixed 3-propyl
substituent, were identified as a new class of potent, selective
adenosine A(1) receptor antagonists. For example, compound 14 (8-butyl-substituted)
exhibits a K(i) value of 13.8 nM at human A(1) receptors. A selection
of the most potent compounds was investigated in (35)SGTPgammaS
binding assays and showed inverse agonistic activity. Their efficacy
was generally lower than that of the full inverse agonist DPCPX,
and depended on subtle structural changes. Some of the new compounds
belong to the most potent and selective A(1) antagonists described
to date.
@article{Weyler2006,
abstract = {The structure-activity relationships of xanthine derivatives related
to the adenosine A(1) receptor antagonists 8-cyclopentyl-1,3-dipropylxanthine
(DPCPX) and 1,3-dipropyl-8-(3-noradamantyl)xanthine (KW3902) were
investigated by focusing on variations of the 3-substituent. Aromatic
residues were well tolerated by the A(1) receptor in that position.
A moderate effect of stereochemistry was found for the 3-(1-phenylethyl)-substituted
analogue of DPCPX (S>R) at A(1) and A(3) receptors, whereas the opposite
stereoselectivity was observed at the A(2) receptor subtypes. A 3-hydroxypropyl
substituent was found to be optimal for high A(1) affinity and selectivity.
The most potent compound of the present series was 1-butyl-3-(3-hydroxypropyl)-8-(3-noradamantyl)xanthine
(10 c), which exhibits a K(i) value of 0.124 nM at rat, and 0.7 nM
at human adenosine A(1) receptors, combined with high selectivity
(>>200-fold) versus the other receptor subtypes. The similarly potent
8-cyclopentyl-3-(3-hydroxypropyl)-1-propylxanthine was converted
into a water-soluble phosphate prodrug, which may become a useful
pharmacological tool for in vivo studies. 8-Alkyl-2-(3-noradamantyl)pyrimido[1,2,3-cd]purine-8,10-diones,
which can be envisaged as xanthine analogues with a fixed 3-propyl
substituent, were identified as a new class of potent, selective
adenosine A(1) receptor antagonists. For example, compound 14 (8-butyl-substituted)
exhibits a K(i) value of 13.8 nM at human A(1) receptors. A selection
of the most potent compounds was investigated in [(35)S]GTPgammaS
binding assays and showed inverse agonistic activity. Their efficacy
was generally lower than that of the full inverse agonist DPCPX,
and depended on subtle structural changes. Some of the new compounds
belong to the most potent and selective A(1) antagonists described
to date.},
added-at = {2010-12-14T18:12:02.000+0100},
author = {Weyler, S. and Fulle, F. and Diekmann, M. and Schumacher, B. and Hinz, S. and Klotz, K. N. and Muller, C. E.},
biburl = {https://www.bibsonomy.org/bibtex/2ee816cee8533f2029e42a81a9272d9de/pharmawuerz},
endnotereftype = {Journal Article},
interhash = {59f54fa3965b7a4b6303d1fc51059f9f},
intrahash = {ee816cee8533f2029e42a81a9272d9de},
issn = {1860-7179 (Print)},
journal = {ChemMedChem},
keywords = {& A1/*antagonists Adamantane/*analogs Adenosine Animals Cultured Humans Phosphates/chemistry Prodrugs/chemistry/*pharmacology Rats Relationship Solubility Structure-Activity Water/chemistry Xanthine/*chemistry Xanthines/chemistry/*pharmacology derivatives/chemistry/pharmacology inhibitors Receptor Cell},
month = Aug,
note = {Weyler, Stefanie Fulle, Friederike Diekmann, Martina Schumacher,
Britta Hinz, Sonja Klotz, Karl-Norbert Muller, Christa E Research
Support, Non-U.S. Gov't Germany ChemMedChem ChemMedChem. 2006 Aug;1(8):891-902.},
number = 8,
pages = {891-902},
shorttitle = {Improving potency, selectivity, and water solubility of adenosine
A1 receptor antagonists: xanthines modified at position 3 and related
pyrimido[1,2,3-cd]purinediones},
timestamp = {2010-12-14T18:20:51.000+0100},
title = {Improving potency, selectivity, and water solubility of adenosine
A1 receptor antagonists: xanthines modified at position 3 and related
pyrimido[1,2,3-cd]purinediones},
url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16902942},
volume = 1,
year = 2006
}