7-Oxo-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamides as selective CB(2) cannabinoid receptor ligands: structural investigations around a novel class of full agonists.
Cannabinoid receptor agonists have gained attention as potential therapeutic targets of inflammatory and neuropathic pain. Here, we report the identification and optimization of a series of 7-oxo-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide derivatives as a novel chemotype of selective cannabinoid CB(2) receptor agonists. Structural modifications led to the identification of several compounds as potent and selective cannabinoid receptor agonists (20, hCB(2)K(i) = 2.5 nM, SI = 166; 21, hCB(2)K(i) = 0.81 nM, SI = 383; 38, hCB(2)K(i) = 15.8 nM, SI > 633; 56, hCB(2)K(i) = 8.12 nM, SI > 1231; (R)-58, hCB(2)K(i) = 9.24 nM, SI > 1082). The effect of a chiral center on the biological activity was also investigated, and it was found that the (R)-enantiomers exhibited greater affinity at the CB(2) receptor than the (S)-enantiomers. In 3,5-cyclic adenosine monophosphate assays, the novel series behaved as agonists, exhibiting functional activity at the human CB(2) receptor.
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy. Baraldi@unife.it
Pier Giovanni
PG
Baraldi
Giulia
G
Saponaro
Allan R
AR
Moorman
Romeo
R
Romagnoli
Delia
D
Preti
Stefania
S
Baraldi
Emanuela
E
Ruggiero
Katia
K
Varani
Martina
M
Targa
Fabrizio
F
Vincenzi
Pier Andrea
PA
Borea
Mojgan
M
Aghazadeh Tabrizi
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism*; D013379:Substrate Specificity
D008024:Ligands; D011804:Quinolines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2