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.
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.
Pasquini
Serena
S
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy.
Botta
Lorenzo
L
Semeraro
Teresa
T
Mugnaini
Claudia
C
Ligresti
Alessia
A
Palazzo
Enza
E
Maione
Sabatino
S
Di Marzo
Vincenzo
V
Corelli
Federico
F
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
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