title: Structure-activity relationships of adenine and deazaadenine derivatives as ligands for adenine receptors, a new purinergic receptor family.
abstract: Adenine derivatives bearing substituents in the 2-, N(6)-, 7-, 8-, and/or 9-position and a series of deazapurines were synthesized and investigated in [(3)H]adenine binding studies at the adenine receptor in rat brain cortical membrane preparations (rAde1R). Steep structure-activity relationships were observed. Substitution in the 8-position (amino, dimethylamino, piperidinyl, piperazinyl) or in the 9-position (2-morpholinoethyl) with basic residues or introduction of polar substituents at the 6-amino function (hydroxy, amino, acetyl) represented the best modifications. Functional evaluation of selected adenine derivatives in adenylate cyclase assays at 1321N1 astrocytoma cells stably expressing the rAde1R showed that all compounds investigated were agonists or partial agonists. A subset of compounds was additionally investigated in binding studies at human embryonic kidney (HEK293) cells, which also express a high-affinity adenine binding site. Structure-affinity relationships at the human cell line were similar to those at the rAde1R, but not identical. In particular, N(6)-acetyladenine (25, K(i) rat: 2.85 microM; K(i) human: 0.515 microM) and 8-aminoadenine (33, K(i) rat: 6.51 microM; K(i) human: 0.0341 microM) were much more potent at the human as compared to the rat binding site. The new AdeR ligands may serve as lead structures and contribute to the elucidation of the functions of the adenine receptor family.
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Borrmann
authors.forename: Aliaa
authors.initials: A
authors.lastname: Abdelrahman
authors.forename: Rosaria
authors.initials: R
authors.lastname: Volpini
authors.forename: Catia
authors.initials: C
authors.lastname: Lambertucci
authors.forename: Edgars
authors.initials: E
authors.lastname: Alksnis
authors.forename: Simone
authors.initials: S
authors.lastname: Gorzalka
authors.forename: Melanie
authors.initials: M
authors.lastname: Knospe
authors.forename: Anke C
authors.initials: AC
authors.lastname: Schiedel
authors.forename: Gloria
authors.initials: G
authors.lastname: Cristalli
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D001254:Astrocytoma / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000737:chemistry; D006801:Humans; D008024:Ligands; D011485:Protein Binding; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014372:Tubercidin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D008024:Ligands; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D000225:Adenine; D014372:Tubercidin