title: Thienylpyrazoloquinolines: potent agonists and inverse agonists to benzodiazepine receptors.
abstract: 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.
authors.affiliation: Division of Organic Chemistry, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Takada
authors.forename: H
authors.initials: H
authors.lastname: Shindo
authors.forename: T
authors.initials: T
authors.lastname: Sasatani
authors.forename: N
authors.initials: N
authors.lastname: Chomei
authors.forename: A
authors.initials: A
authors.lastname: Matsushita
authors.forename: M
authors.initials: M
authors.lastname: Eigyo
authors.forename: K
authors.initials: K
authors.lastname: Kawasaki
authors.forename: S
authors.initials: S
authors.lastname: Murata
authors.forename: Y
authors.initials: Y
authors.lastname: Takahara
authors.forename: H
authors.initials: H
authors.lastname: Shintaku
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D003975:Diazepam / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000378:metabolism*
chemical_list: D011720:Pyrazoles; D011804:Quinolines; D011963:Receptors, GABA-A; D013876:Thiophenes; D003975:Diazepam