2-(5-Alkylthien-3-yl)-(1),2-(4-alkylthien-2-yl)-(2), and 2-(5-alkylthien-2-yl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolines (3) were prepared in four steps starting from ethyl 4-chloroquinoline-3-carboxylate (4) and hydrazinothiophene-carboxylates 5, 8, and 9. All the assayed compounds possessed high affinities for benzodiazepine receptors (Ki = 0.3-2.6 nM). The activities of agonists and inverse agonists were assessed on the basis of inhibition or facilitation of pentylenetetrazole-induced convulsions, respectively. Introduction of alkyl groups of different sizes into the unsubstituted inverse agonistic compounds results in a corresponding shift in the activity from an inverse agonist to an antagonist to an agonist. The susceptibility of such a shift increases in the order of 1 less than 2 less than 3. This tendency may be explained by slight differences in the geometry of the alkyl substituents among the three series.
Synthesis and structure-activity relationships of a series of 2-(thien-3-yl)- and 2-(thien-2-yl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-ones are reported. A number of the compounds possessed 1 order of magnitude higher affinity for the receptors than diazepam. Planarity was one of the structural requirements for binding to benzodiazepine receptors. The activities of agonists and inverse agonists were assessed on the basis of inhibition or facilitation of the pentylenetetrazole-induced convulsions, respectively. Thien-3-yl compounds exhibited inverse agonist activity whereas thien-2-yl analogues with a 5'-alkyl group showed agonist activity. Substitution on the quinoline moiety did not enhance in vivo activity. The most potent compounds were the 5-methylthien-3-yl derivative 6a as an inverse agonist and the 5-methylthien-2-yl compound 13a as an agonist.
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