2-Arylpyrazolo[4,3-c]quinolin-3-ones: a novel agonist, a partial agonist and an antagonist of benzodiazepines

Journal of Medicinal Chemistry
1982.0

Abstract

In summary, except for the tumor suppression test, compound 3 represents the minimal active structure essential for eliciting the effects in the immunostimulating assays so far examined. Its derivatives 4 and 5 were found to be capable of increasing resistance to bacterial infection as efficiently as 1, and 5 proved to possess the unique tumor-suppression ability lacking in 1. On the basis of these activity profiles, 4 and 5 are now undergoing more detailed examinations for antiinfectious and antitumor effectiveness, respectively. We wish to report on three novel 2-arylpyrazolo[4,3-c]quinolin-3-ones, all of which possess extremely high affinity for the benzodiazepine receptors, yet the first (3a) is a very potent antagonist of diazepam, the second (3b) is a safe antianxiety agent, and the third (3c) is a hitherto unknown partial agonist of the benzodiazepine receptor. Compounds 3a-c have an order of magnitude greater affinity for the benzodiazepine receptors than diazepam, are well absorbed and cross the blood-brain barrier as evidenced by the in vivo ID50 values. In the rat metrazol anticonvulsant test, 3b was more potent than diazepam, whereas 3a was completely inactive, and 3c gave a U-shaped dose-response curve with a peak effect at 10 mg/kg. 3a blocked the anticonvulsant activity of diazepam at 3 mg/kg, and 3c showed a hint of the antagonism at 30 mg/kg. Antianxiety effect of 3b was confirmed by the Cook-Davidson behavior test. It is apparent from these biological data that 3a is a potent benzodiazepine antagonist, 3b is diazepam-like both in the anticonvulsant test and in the anticonflict behavioral test, and 3c acts as an agonist (diazepam-like) at low doses and as an antagonist at higher doses. All three compounds have very unique potentials as medicinal agents. The real advantage of 3b over currently marketed benzodiazepines lies in its total lack of neurological deficits, as evidenced by no activity in the rat rotarod test up to a 300 mg/kg PO dose.

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