Synthesis, binding studies, and structure activity relationships of 1-aryl- and 2-aryl[1]benzopyranopyrazol-4-ones, central benzodiazepine receptor ligands

Journal of Medicinal Chemistry
1988.0

Abstract

Benzodiazepines are important therapeutic agents which have been the object of intense investigation. These drugs exert their main actions, such as anxiolytic, hypnotic, anticonvulsant, and muscle relaxant effects, on the central nervous system, by interacting with special neuronal membrane proteins, the benzodiazepine receptors, which are at least partly located in GABA-ergic synapses. A number of synthetic compounds with diverse structures have been found to have affinity for the benzodiazepine receptors. These non-benzodiazepine compounds with affinity for the benzodiazepine receptors are important tools for finding out the physiological properties and the structural requirements of the recognition site of the receptor itself. Following our previous research on the syntheses and binding studies on pyrazoloquinoline derivatives interacting with the central benzodiazepine receptors, we hereby report the syntheses and binding studies of a series of 1,4-dihydro-1-aryl-3-methyl[1]benzopyrano[3,4-d]pyrazol-4-ones 1 and a series of 2,4-dihydro-2-aryl-3-methyl[1]benzopyrano[4,3-c]pyrazol-6-ones 2. Both series, 1 and 2, are isosteres of the previously reported ones since the quinoline NH has been replaced by the oxygen of the [1]benzopyrano moiety. The syntheses of series 1 and 2 compounds were achieved by cyclizing the arylhydrazones 3a-o of 3-acetyl-4-hydroxycoumarin either with p-toluenesulfonic acid in refluxing xylene or with arylhydrazine hydrochloride in refluxing acetic acid. The amino derivatives 1p-r were obtained by catalytic reduction of the corresponding nitro compounds 1i-k. All of the synthesized compounds were tested for their ability to displace specific [3H]flunitrazepam from bovine brain membranes. First, a single concentration of the test compounds was examined, followed by the examination of the IC50 values from log-probit plots of the most active ones. From our results it appears that, in agreement with our previous findings on pyrazoloquinoline series, a prerequisite for showing a satisfactory inhibiting potency is the presence of an aryl substituent in position 1. Most of the 1-aryl derivatives of series 1 interact with the benzodiazepine receptor with an inhibiting potency which ranks between chlordiazepoxide and diazepam, while their 2-aryl isomers 2 show very poor affinity for the benzodiazepine receptor binding sites. The important role played by the position of the substituent on the 1-phenyl ring is also confirmed, with the binding potency decreasing when the substituent on the 1-phenyl ring is displaced from the meta to the para to the ortho position. The meta-substituted 1-(3,5-dimethylphenyl) derivative 1o shows an IC50 value of 0.065 μM, about 12 times lower than that of chlordiazepoxide and only 2.6 times higher than that of diazepam. The varying trends of the amino derivatives 1p-r may be due to the presence of the basic amino group. The replacement of the methyl group at position 3 with phenyl results in the complete lack of binding affinity on the part of compound 4. In conclusion, it has to be noted that it is the position of the substituent on the 1-phenyl ring, and not its nature, that influences binding potency. Most important in these new series of compounds interacting with the benzodiazepine receptor is the fact that the isosteric replacement of the quinoline NH with the benzopyrano oxygen brings about an enhancement of the inhibiting potency compared to pyrazoloquinoline derivatives.

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