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Pyrazolopyridines: Effect of structural alterations on activity at adenosine‐ and GABA A ‐receptors
Author(s) -
Shi Dan,
Padgett William L.,
Hutchinson Kira D.,
Moore Stacey P.,
Daly John W.
Publication year - 1997
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199709)42:1<41::aid-ddr4>3.0.co;2-r
Subject(s) - gabaa receptor , allosteric regulation , binding site , chemistry , competitive antagonist , receptor , antagonist , stereochemistry , biophysics , pharmacology , biochemistry , biology
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 1 ‐ and A 2A ‐adenosine receptors and at GABA‐, benzodiazepine‐, and picrotoxinin‐ binding sites of the GABA A ‐receptor‐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 A ‐receptor‐channel. Drug Dev. Res. 42:41–56, 1997. © 1997 Wiley‐Liss, Inc. This article is a US Government work and, as such, is in the public domain in the United States of America.