title: Investigations on the 4-quinolone-3-carboxylic acid motif. 3. Synthesis, structure-affinity relationships, and pharmacological characterization of 6-substituted 4-quinolone-3-carboxamides as highly selective cannabinoid-2 receptor ligands.
abstract: A set of quinolone-3-carboxamides 2 bearing diverse substituents at position 1, 3, and 6 of the bicyclic nucleus was prepared. Except for six compounds exhibiting Ki>100 nM, all the quinolone-3-carboxamides 2 proved to be high affinity CB2 ligands, with Ki values ranging from 73.2 to 0.7 nM and selectivity [SI=Ki(CB1)/Ki(CB2)] varying from >14285 to 1.9, with only 2ah exhibiting a reverse selectivity (SI<1). In the formalin test of peripheral acute and inflammatory pain in mice, 2ae showed analgesic activity that was antagonized by a selective CB2 antagonist. By contrast, 2e was inactive per se and antagonized the effect of a selective CB2 agonist. Finally, 2g and 2p exhibited CB2 inverse agonist-like behavior in this in vivo test. However, two different functional assays carried out in vitro on 2e and 2g indicated for both compounds an overall inverse agonist activity at CB2 receptors.
authors: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy.
authors: Serena
authors: S
authors: Pasquini
authors: Alessia
authors: A
authors: Ligresti
authors: Claudia
authors: C
authors: Mugnaini
authors: Teresa
authors: T
authors: Semeraro
authors: Lavinia
authors: L
authors: Cicione
authors: Maria
authors: M
authors: De Rosa
authors: Francesca
authors: F
authors: Guida
authors: Livio
authors: L
authors: Luongo
authors: Maria
authors: M
authors: De Chiaro
authors: Maria Grazia
authors: MG
authors: Cascio
authors: Daniele
authors: D
authors: Bolognini
authors: Pietro
authors: P
authors: Marini
authors: Roger
authors: R
authors: Pertwee
authors: Sabatino
authors: S
authors: Maione
authors: Vincenzo
authors: V
authors: Di Marzo
authors: Federico
authors: F
authors: Corelli
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D054314:Drug Inverse Agonism; D006801:Humans; D008024:Ligands; D051379:Mice; D010147:Pain Measurement; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000700:Analgesics; D008024:Ligands; D015363:Quinolones; D043885:Receptor, Cannabinoid, CB2