title: Investigations on the 4-quinolone-3-carboxylic acid motif. 2. Synthesis and structure-activity relationship of potent and selective cannabinoid-2 receptor agonists endowed with analgesic activity in vivo.
abstract: Quinolone-3-carboxamides 11 bearing at position 5, 6, 7, or 8 diverse substituents such as halides, alkyl, aryl, alkoxy, and aryloxy groups differing in their steric/electronic properties, were prepared. The new compounds were tested in vitro for CB1 and CB2 receptor affinity in comparison with the reference compounds rimonabant and SR144528. The tested compounds exhibited CB2 affinity in the range from 55.9 to 0.8 nM and CB1 affinity in the range from >10,000 to 5.3 nM, with selectivity indeces [Ki(CB1)/Ki(CB2)] varying from >2666.6 to 1.23. On the basis of the structure-selectivity relationship developed, the presence of a substituent at C6/C8 or C7 well accounts for the high or low CB2 selectivity, respectively. Compound 11c, characterized by high CB2 affinity and selectivity, showed analgesic activity in the formalin test of acute peripheral and inflammatory pain in mice as a result of selective CB2 agonistic activity.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Pasquini
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Botta
authors.forename: Teresa
authors.initials: T
authors.lastname: Semeraro
authors.forename: Claudia
authors.initials: C
authors.lastname: Mugnaini
authors.forename: Alessia
authors.initials: A
authors.lastname: Ligresti
authors.forename: Enza
authors.initials: E
authors.lastname: Palazzo
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Federico
authors.initials: F
authors.lastname: Corelli
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D051379:Mice; D010146:Pain / Q000188:drug therapy; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D002264:Carboxylic Acids; C580859:N-(adamantan-1-yl)-4-oxo-1-pentyl-6-phenyl-1,4-dihydroquinoline-3-carboxamide; D015363:Quinolones; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000218:Adamantane