Pyrazolopyridines: Effect of structural alterations on activity at adenosine- and GABAA-receptors

✍ Scribed by Dan Shi; William L. Padgett; Kira D. Hutchinson; Stacey P. Moore; John W. Daly

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 403 KB
• Volume: 42
• Category: Article
• ISSN: 0272-4391
• DOI: 10.1002/(sici)1098-2299(199709)42:1<41::aid-ddr4>3.0.co;2-r

✦ Synopsis

A series of 4-substituted 1H-pyrazolo [3,4-b]pyridine-5-carboxylic acid derivatives related in structure to the putative anxiolytics cartazolate, tracazolate, and etazolate were assessed for affinity at A 1and A 2A -adenosine receptors and at GABA-, benzodiazepine-, and picrotoxinin-binding sites of the GABA Areceptor-channel. None of the derivatives had markedly greater affinity at A 1 -receptors than cartazolate (K i -0.5 µM), but many had markedly lower affinity than cartazolate (K i -1.5 µM) at A 2A -receptors. At the benzodiazepine-binding site of GABA A -receptors some of the derivatives enhanced [ 3 H]diazepam binding, as did cartazolate and GABA, some had no effect and some inhibited binding. Most of the derivatives inhibited binding of the benzodiazepine-antagonist [ 3 H]Ro 15-1788. At the GABA-binding site, only a few of the derivatives inhibited binding of the antagonist [ 3 H]SR-95531, as did GABA. At the picrotoxinin-binding site, many inhibited binding of [ 35 S]TBPS, but none were as potent as cartazolate or GABA. Analysis of the interactions indicates that stimulation of [ 3 H]diazepam binding is allosteric and results from binding of the pyrazolopyridine at the GABA site or a subdomain of that site, while inhibition of [ 3 H]Ro 15-1788 binding is competitive and due to binding at the benzodiazepine site. Inhibition of [ 35 S]TBPS binding at the picrotoxinin-channel site appears to be allosteric through the GABA site and/or by direct competition at the channel site. Alterations in structure markedly alter the affinities of pyrazolopyridines at such sites on the GABA Areceptor-channel.