Thienylpyrazoloquinolines with high affinity to benzodiazepine receptors: continuous shift from inverse agonist to agonist properties depending on the size of the alkyl substituent.
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.
Shindo
H
H
Division of Organic Chemistry, Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Takada
S
S
Murata
S
S
Eigyo
M
M
Matsushita
A
A
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D003975:Diazepam / Q000037:antagonists & inhibitors; D004357:Drug Synergism; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010433:Pentylenetetrazole; D011720:Pyrazoles / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology
D011720:Pyrazoles; D011804:Quinolines; D011963:Receptors, GABA-A; D013876:Thiophenes; D003975:Diazepam; D010433:Pentylenetetrazole