PYRAZOLOPYRIDINES - EFFECT OF STRUCTURAL ALTERATIONS ON ACTIVITY AT ADENOSINE-RECEPTOR AND GABA(A)-RECEPTOR

A series of 4-substituted 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid derivatives related in structure to the putative anxiolytics cartazol ate, tracazolate, and etazolate were assessed for affinity at A(1)- an d A(2A)-adenosine receptors and at GABA-, benzodiazepine-, and picroto xin in-binding sites of the GABA(A)-receptor-channel. None of the deri vatives had markedly greater affinity al Al-receptors than cartazolate (K-i-0.5 mu M), but many had markedly lower affinity than cartazolate (K-i-1.5 mu M) at A(2A)-receptors. At the benzodiazepine-binding site of GABA(A)-receptors some of the derivatives enhanced [H-3]diazepam b inding, as did cartazolate and GABA, some had no effect and some inhib ited binding. Most of the derivatives inhibited binding of the benzodi azepine-antagonist [H-3]Ro 15-1788. At the GABA-binding site, only a f ew of the derivatives inhibited binding of the antagonist [H-3]SR-9553 1, as did GABA. Al the picrotoxinin-binding sire, many inhibited bindi ng of [S-35]TBPS, but none were as potent as cartazolate or GABA. Anal ysis of the interactions indicates that stimulation of [H-3]diazepam b inding is allosteric and results from binding of the pyrazolopyridine at the GABA site or a subdomain of that site, while inhibition of [H-3 ]Ro 15-1788 binding is competitive and due to binding at the benzodiaz epine site. Inhibition of [S-35]TBPS binding at the picrotoxinin-chann el site appears to be allosteric through the GABA site and/or by direc t competition at the channel site. Alterations in structure markedly a lter the affinities of pyrazolopyridines at such sites on the GABA(A)- receptor-channel. (C) 1997 Wiley-Liss, Inc.dagger.