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Synthesis and biological evaluation of disubstituted N6- cyclopentyladenine analogues: The search for a neutral antagonist with high affinity for the adenosine A1 receptor

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Author: Ligt, R.A.F. de · Klein, P.A.M. van der · Frijtag Drabbe Künzel, J.K. von · Lorenzen, A. · El Maate, F.A. · Fujikawa, S. · Westhoven, R. van · Hoven, T. van den · Brussee, J. · Ijzerman, A.P.
Type:article
Date:2004
Institution: TNO Voeding
Source:Bioorganic and Medicinal Chemistry, 1, 12, 139-149
Identifier: 237589
doi: doi:10.1016/j.bmc.2003.10.023
Keywords: Biology Toxicology · Physiological Sciences · [35S]GTPγS binding · Adenosine A1 receptor · Inverse agonism · N-0840 derivatives · Neutral antagonist · 8 bromo 9 methyladenine · 8 bromo n 6 cyclopentyl 9 methyladenine · 8 bromo n 6 cyclopentyl 9 propyladenine · 9 allyl 8 bromo n 6 cyclopentyladenine · 9 allyl n 6 cyclopentyl 8 methoxyadenine · adenine derivative · adenosine A1 receptor antagonist · luf 5666 · luf 5668 · luf 5669 · luf 5674 · n 0840 · n 6 cyclopentyl 8 (ethylthio) 9 methyladenine · n 6 cyclopentyl 8 (n ethyl n butylamino) 9 methyladenine · n 6 cyclopentyl 8 (n methyl n ethylamino) 9 methyladenine · n 6 cyclopentyl 8 (n methyl n propylamino) 9 methyladenine · n 6 cyclopentyl 8 (n methylamino) 9 methyladenine · n 6 cyclopentyl 8 (n methylisopropylamino) 9 methyladenine · n 6 cyclopentyl 8 (n piperidino) 9 methyladenine · n 6 cyclopentyl 8 (n pyrrolidino) 9 methyladenine · n 6 cyclopentyl 8 (n,n diethylamino) 9 methyladenine · n 6 cyclopentyl 8 ethoxy 9 methyladenine · n 6 cyclopentyl 8 isopropoxy 9 methyladenine · n 6 cyclopentyl 8 methoxy 9 methyladenine · n 6 cyclopentyl 8 methoxy 9 propyladenine · n 6 cyclopentyl 9 methyl 8 oxoadenine · n 6 cyclopentyl 9 methyl 8 propoxyadenine · n 6 cyclopentyl 9 methyladenine · unclassified drug · article · binding affinity · drug determination · drug synthesis · drug tolerability · receptor affinity · substitution reaction · Adenine · Adenosine · Animals · Cell Line · CHO Cells · Cricetinae · Drug Evaluation, Preclinical · Humans · Receptor, Adenosine A1

Abstract

Novel 3,8- and 8,9-disubstituted N6-cyclopentyladenine derivatives were synthesised in moderate overall yield from 6-chloropurine. The derivatives were made in an attempt to find a new neutral antagonist with high affinity for adenosine A1 receptors. N6-Cyclopentyl-9- methyladenine (N-0840) was used as a lead compound. Binding affinities of the new analogues were determined for human adenosine A1 and A 3 receptors. Their intrinsic activity was assessed in [ 35S]GTPγS binding experiments. Elongation of the 9-methyl of N-0840 to a 9-propyl substituent was very well tolerated. A 9-benzyl group, on the other hand, caused a decrease in adenosine A1 receptor affinity. Next, the 8-position was examined in detail, and affinity was increased with appropriate substitution. Most derivatives were A1-selective and 20 of the new compounds (6-9, 15-21, 23-26, 28, 31, 33, 35, and 36) had higher adenosine A1 receptor affinity than the reference substance, N-0840. Compound 31 (N6-cyclopentyl-8-(N-methylisopropylamino)-9- methyladenine, LUF 5608) had the highest adenosine A1 receptor affinity, 7.7 nM. In the [35S]GTPγS binding experiments, derivatives 5, 14, 22, 23, 25, 26, 33 and 34 did not significantly change basal [35S]GTPγS binding, thus behaving as neutral antagonists. Moreover, four of these compounds (23, 25, 26, and 33) displayed a 4- to 10-fold increased adenosine A1 receptor affinity (75-206 nM) compared to N-0840 (852 nM). In summary, we synthesised a range of N-0840 analogues with higher affinity for adenosine A1 receptors. In addition, four new derivatives, LUF 5666 (23), LUF 5668 (25), LUF 5669 (26) and LUF 5674 (33), behaved as neutral antagonists when tested in [ 35S]GTPγS binding studies. Thus, these compounds have improved characteristics as neutral adenosine A1 receptor antagonists. © 2003 Elsevier Ltd. All rights reserved.