9-Ethyladenine derivatives as adenosine receptor antagonists: 2- and 8-substitution results in distinct selectivities.
9-Ethyladenine was used as the basis for a series of non-xanthine adenosine receptor antagonists at human adenosine receptors. The adenine-based compounds were substituted in 2- or 8-position with a variety of side chains including some aryl or arylalkynyl groups previously tested as 2-substituents in adenosine and 5'-N-ethylcarboxamidoadenosine (NECA) for their effect on agonist affinity. The affinity of the novel compounds was tested in radioligand binding assays (A1, A2A and A3) and inhibition of NECA-stimulated adenylyl cyclase activity (A2B) in membranes prepared from CHO cells stably transfected with the respective human receptor subtype. High affinity antagonists were identified for A1 (9-ethyl-8-phenyl-9H-adenine, compound 2; 6-(1-butylamino)-9-ethyl-8-phenyl-9H-purine, compound 3), A2A (8-ethoxy-9-ethyladenine; compound 8) and A3 (9-ethyl-8-phenylethynyl-9H-adenine, compound 5) with selectivities versus other receptor subtypes in the range of 10 to 600. These results demonstrate that adenine is a useful template for further development of high-affinity antagonists with distinct receptor selectivity profiles.
Klotz
Karl-Norbert
KN
Institut für Pharmakologie und Toxikologie, Universität Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany. klotz@toxi.uni-wuerzburg.de
Kachler
Sonja
S
Lambertucci
Catia
C
Vittori
Sauro
S
Volpini
Rosaria
R
Cristalli
Gloria
G
D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1 / Q000737:chemistry / Q000502:physiology; D013329:Structure-Activity Relationship
D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; C001172:9-ethyladenine; D000225:Adenine