5'-Carbamoyl derivatives of 2'-C-methyl-purine nucleosides as selective
A1 adenosine receptor agonists: affinity, efficacy, and selectivity
for A1 receptor from different species
L. Cappellacci, P. Franchetti, P. Vita, R. Petrelli, A. Lavecchia, B. Costa, F. Spinetti, C. Martini, K. Klotz, and M. Grifantini. Bioorg Med Chem, 16 (1):
336-53(January 2008)Cappellacci, Loredana Franchetti, Palmarisa Vita, Patrizia Petrelli,
Riccardo Lavecchia, Antonio Costa, Barbara Spinetti, Francesca Martini,
Claudia Klotz, Karl-Norbert Grifantini, Mario Research Support, Non-U.S.
Gov't England Bioorganic & medicinal chemistry Bioorg Med Chem.
2008 Jan 1;16(1):336-53. Epub 2007 Sep 22..
Abstract
A series of 5'-carbamoyl and 5'-thionocarbamoyl derivatives of 2'-C-methyl
analogues of the A(1) adenosine receptor (A(1)AR) full agonists N(6)-cyclopentyladenosine
(CPA), 2-chloro-N(6)-cyclopentyladenosine (CCPA), N(6)-3-(R)-tetrahydrofuranyladenosine
(tecadenoson), and 2-chloro analogue (2-Cl-tecadenoson) was synthesized
and evaluated for their affinity for adenosine receptor subtypes
from bovine, porcine, and human species. In the N(6)-cyclopentylamino
series, the 5'-substituted derivatives showed a reduced affinity
at the bovine A(1)AR compared to the parent compounds; however, the
selectivity for A(1) versus A(2A) receptor was retained or increased.
The corresponding N(6)-3-(R)-tetrahydrofuranylamino analogues displayed
a very low affinity toward the bovine A(1)AR. The 5'-methylthionocarbamoyl
derivative of 2'-Me-CCPA showed the best affinity at porcine A(1)AR
with a K(i) value of 13 nM. At human AR subtypes tecadenoson derivatives
showed 2.3- to 5-fold lower affinity at A(1)AR and very low affinity
at the other subtypes (A(2A), A(2B), and A(3)) compared to the corresponding
N(6)-cyclopentyl analogues. The 5'-carbamoyl and 5'-thionocarbamoyl
derivatives of 2'-Me-CCPA 3, 4, 7 and tecadenoson derivative 12 were
found to be partial A(1) agonists at the porcine receptor. Docking
studies explained the lower affinity of N(6)-3-(R)-tetrahydrofuranyl-substituted
compounds at bovine A(1)AR compared to that of N(6)-cyclopentyl analogues,
showing that the oxygen of the tetrahydrofuranyl ring establishes
unfavorable electrostatic interactions with the CO oxygen of Asn254.
The low binding affinity of the 2'-C-methyl-N(6)-3-(R)-tetrahydrofuranyl
adenosine analogues at human A(1)AR may be ascribed to the presence
of unfavorable interactions between the hydrophilic tetrahydrofuranyl
ring and the surrounding hydrophobic residues Leu250 (TM6) and Ile274
(TM7).
5'-Carbamoyl derivatives of 2'-C-methyl-purine nucleosides as selective
A1 adenosine receptor agonists: affinity, efficacy, and selectivity
for A1 receptor from different species
%0 Journal Article
%1 Cappellacci2008
%A Cappellacci, L.
%A Franchetti, P.
%A Vita, P.
%A Petrelli, R.
%A Lavecchia, A.
%A Costa, B.
%A Spinetti, F.
%A Martini, C.
%A Klotz, K. N.
%A Grifantini, M.
%D 2008
%J Bioorg Med Chem
%K A1/*agonists Adenosine Animals Binding Carbamates/*chemistry Computer Electricity Humans Hydrophobicity Models, Molecular Nucleosides/*chemistry/*pharmacology Protein Purine Relationship Simulation Static Structure-Activity Swine Receptor
%N 1
%P 336-53
%T 5'-Carbamoyl derivatives of 2'-C-methyl-purine nucleosides as selective
A1 adenosine receptor agonists: affinity, efficacy, and selectivity
for A1 receptor from different species
%U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17933541
%V 16
%X A series of 5'-carbamoyl and 5'-thionocarbamoyl derivatives of 2'-C-methyl
analogues of the A(1) adenosine receptor (A(1)AR) full agonists N(6)-cyclopentyladenosine
(CPA), 2-chloro-N(6)-cyclopentyladenosine (CCPA), N(6)-3-(R)-tetrahydrofuranyladenosine
(tecadenoson), and 2-chloro analogue (2-Cl-tecadenoson) was synthesized
and evaluated for their affinity for adenosine receptor subtypes
from bovine, porcine, and human species. In the N(6)-cyclopentylamino
series, the 5'-substituted derivatives showed a reduced affinity
at the bovine A(1)AR compared to the parent compounds; however, the
selectivity for A(1) versus A(2A) receptor was retained or increased.
The corresponding N(6)-3-(R)-tetrahydrofuranylamino analogues displayed
a very low affinity toward the bovine A(1)AR. The 5'-methylthionocarbamoyl
derivative of 2'-Me-CCPA showed the best affinity at porcine A(1)AR
with a K(i) value of 13 nM. At human AR subtypes tecadenoson derivatives
showed 2.3- to 5-fold lower affinity at A(1)AR and very low affinity
at the other subtypes (A(2A), A(2B), and A(3)) compared to the corresponding
N(6)-cyclopentyl analogues. The 5'-carbamoyl and 5'-thionocarbamoyl
derivatives of 2'-Me-CCPA 3, 4, 7 and tecadenoson derivative 12 were
found to be partial A(1) agonists at the porcine receptor. Docking
studies explained the lower affinity of N(6)-3-(R)-tetrahydrofuranyl-substituted
compounds at bovine A(1)AR compared to that of N(6)-cyclopentyl analogues,
showing that the oxygen of the tetrahydrofuranyl ring establishes
unfavorable electrostatic interactions with the CO oxygen of Asn254.
The low binding affinity of the 2'-C-methyl-N(6)-3-(R)-tetrahydrofuranyl
adenosine analogues at human A(1)AR may be ascribed to the presence
of unfavorable interactions between the hydrophilic tetrahydrofuranyl
ring and the surrounding hydrophobic residues Leu250 (TM6) and Ile274
(TM7).
@article{Cappellacci2008,
abstract = {A series of 5'-carbamoyl and 5'-thionocarbamoyl derivatives of 2'-C-methyl
analogues of the A(1) adenosine receptor (A(1)AR) full agonists N(6)-cyclopentyladenosine
(CPA), 2-chloro-N(6)-cyclopentyladenosine (CCPA), N(6)-[3-(R)-tetrahydrofuranyl]adenosine
(tecadenoson), and 2-chloro analogue (2-Cl-tecadenoson) was synthesized
and evaluated for their affinity for adenosine receptor subtypes
from bovine, porcine, and human species. In the N(6)-cyclopentylamino
series, the 5'-substituted derivatives showed a reduced affinity
at the bovine A(1)AR compared to the parent compounds; however, the
selectivity for A(1) versus A(2A) receptor was retained or increased.
The corresponding N(6)-3-(R)-tetrahydrofuranylamino analogues displayed
a very low affinity toward the bovine A(1)AR. The 5'-methylthionocarbamoyl
derivative of 2'-Me-CCPA showed the best affinity at porcine A(1)AR
with a K(i) value of 13 nM. At human AR subtypes tecadenoson derivatives
showed 2.3- to 5-fold lower affinity at A(1)AR and very low affinity
at the other subtypes (A(2A), A(2B), and A(3)) compared to the corresponding
N(6)-cyclopentyl analogues. The 5'-carbamoyl and 5'-thionocarbamoyl
derivatives of 2'-Me-CCPA 3, 4, 7 and tecadenoson derivative 12 were
found to be partial A(1) agonists at the porcine receptor. Docking
studies explained the lower affinity of N(6)-3-(R)-tetrahydrofuranyl-substituted
compounds at bovine A(1)AR compared to that of N(6)-cyclopentyl analogues,
showing that the oxygen of the tetrahydrofuranyl ring establishes
unfavorable electrostatic interactions with the CO oxygen of Asn254.
The low binding affinity of the 2'-C-methyl-N(6)-3-(R)-tetrahydrofuranyl
adenosine analogues at human A(1)AR may be ascribed to the presence
of unfavorable interactions between the hydrophilic tetrahydrofuranyl
ring and the surrounding hydrophobic residues Leu250 (TM6) and Ile274
(TM7).},
added-at = {2010-12-14T18:12:02.000+0100},
author = {Cappellacci, L. and Franchetti, P. and Vita, P. and Petrelli, R. and Lavecchia, A. and Costa, B. and Spinetti, F. and Martini, C. and Klotz, K. N. and Grifantini, M.},
biburl = {https://www.bibsonomy.org/bibtex/25ca85cda2f60edae818ce440e0bbf634/pharmawuerz},
endnotereftype = {Journal Article},
interhash = {874e54907c5695d3e272b695e4ea2794},
intrahash = {5ca85cda2f60edae818ce440e0bbf634},
issn = {1464-3391 (Electronic) 1464-3391 (Linking)},
journal = {Bioorg Med Chem},
keywords = {A1/*agonists Adenosine Animals Binding Carbamates/*chemistry Computer Electricity Humans Hydrophobicity Models, Molecular Nucleosides/*chemistry/*pharmacology Protein Purine Relationship Simulation Static Structure-Activity Swine Receptor},
month = {Jan 1},
note = {Cappellacci, Loredana Franchetti, Palmarisa Vita, Patrizia Petrelli,
Riccardo Lavecchia, Antonio Costa, Barbara Spinetti, Francesca Martini,
Claudia Klotz, Karl-Norbert Grifantini, Mario Research Support, Non-U.S.
Gov't England Bioorganic \& medicinal chemistry Bioorg Med Chem.
2008 Jan 1;16(1):336-53. Epub 2007 Sep 22.},
number = 1,
pages = {336-53},
shorttitle = {5'-Carbamoyl derivatives of 2'-C-methyl-purine nucleosides as selective
A1 adenosine receptor agonists: affinity, efficacy, and selectivity
for A1 receptor from different species},
timestamp = {2010-12-14T18:22:02.000+0100},
title = {5'-Carbamoyl derivatives of 2'-C-methyl-purine nucleosides as selective
A1 adenosine receptor agonists: affinity, efficacy, and selectivity
for A1 receptor from different species},
url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17933541},
volume = 16,
year = 2008
}