Thienylpyrazoloquinolines with high affinity to benzodiazepine receptors: continuous shift from inverse agonist to agonist properties depending on the size of the alkyl substituent

• Published in: Journal of medicinal chemistry Vol. 32; no. 6; pp. 1213 - 1217
• Main Authors: Shindo, Hirohisa, Takada, Susumu, Murata, Shunji, Eigyo, Masami, Matsushita, Akira
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-06-1989
• Subjects: Animals; Chemical Phenomena; Chemistry; Diazepam - antagonists & inhibitors; Drug Synergism; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Male; Mice; Molecular Structure; Organic chemistry; Pentylenetetrazole; Preparations and properties; Pyrazoles - chemical synthesis; Pyrazoles - metabolism; Pyrazoles - pharmacology; Quinolines - chemical synthesis; Quinolines - metabolism; Quinolines - pharmacology; Receptors, GABA-A - drug effects; Receptors, GABA-A - physiology; Seizures - chemically induced; Structure-Activity Relationship; thienylpyrazoloquinolines; Thiophenes - chemical synthesis; Thiophenes - metabolism; Thiophenes - pharmacology; Sulfur nitrogen heterocycle; Benzodiazepine receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00126a012

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.