1-substituted 4-[chloropyrazolyl][1,2,4]triazolo[4,3-a]quinoxalines: synthesis and structure-activity relationships of a new class of benzodiazepine and adenosine receptor ligands.
Starting from 3-(3-chloro-1H-pyrazol-5-yl)-1H-quinoxalin-2-one (2) a series of substituted [1,2,4]triazolo[4,3-a]quinoxalines (3a-f) was prepared via a multistep reaction sequence. Affinities of the novel derivatives 3a-f for benzodiazepine as well as for adenosine A1- and A2A-receptors of rat brain were determined by radioligand binding assays. 1-Methyl-4-(3-chloro-1H-pyrazol-5-yl) derivative 3a exhibited submicromolar affinity for the benzodiazepine binding site of GABAA receptors (Ki = 340 nM) and was less potent at A1-(Ki = 7.85 microM) and A2A-(Ki = 1.43 microM) adenosine receptors (AR). Derivatives with larger substituents in the 1-position showed reduced binding to benzodiazepine and A2A-AR, but increased A1-AR affinity, the 2-thienylmethyl derivative 3f being the most potent and selective A1-AR ligand of the present series (Ki = 200 nM).
Institute of Pharmaceutical Chemistry, University of Innsbruck, Austria.
B
B
Matuszczak
E
E
Pekala
C E
CE
Müller
D000818:Animals; D058787:GABA-A Receptor Antagonists; D008024:Ligands; D058915:Purinergic P1 Receptor Antagonists; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology
D058787:GABA-A Receptor Antagonists; D008024:Ligands; D058915:Purinergic P1 Receptor Antagonists; D011720:Pyrazoles; D011810:Quinoxalines; D014230:Triazoles