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 CB2 receptor agonists. Structural modifications led to the identification of several compounds as potent and selective cannabinoid receptor agonists (20: hCB2 Ki = 2.5 nM, SI = 166; 21: hCB2 Ki = 0.81 nM, SI = 383; 38: hCB2 Ki = 15.8 nM, SI > 633; 56: hCB2 Ki = 8.12 nM, SI > 1231; (R)-58: hCB2 Ki = 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 CB2 receptor than the (S)-enantiomers. In 3,5-cyclic adenosine monophosphate (cAMP) assays, the novel series behaved as agonists, exhibiting functional activity at the human CB2 receptor.

7-Oxo-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamides as Selective CB2 Cannabinoid Receptor Ligands: Structural Investigations around a Novel Class of Full Agonists

BARALDI, Pier Giovanni;SAPONARO, Giulia;ROMAGNOLI, Romeo;PRETI, Delia;BARALDI, Stefania;RUGGIERO, Emanuela;VARANI, Katia;TARGA, Martina;VINCENZI, Fabrizio;BOREA, Pier Andrea;AGHAZADEH TABRIZI, Mojgan
2012

Abstract

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 CB2 receptor agonists. Structural modifications led to the identification of several compounds as potent and selective cannabinoid receptor agonists (20: hCB2 Ki = 2.5 nM, SI = 166; 21: hCB2 Ki = 0.81 nM, SI = 383; 38: hCB2 Ki = 15.8 nM, SI > 633; 56: hCB2 Ki = 8.12 nM, SI > 1231; (R)-58: hCB2 Ki = 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 CB2 receptor than the (S)-enantiomers. In 3,5-cyclic adenosine monophosphate (cAMP) assays, the novel series behaved as agonists, exhibiting functional activity at the human CB2 receptor.
Baraldi, Pier Giovanni; Saponaro, Giulia; A. R., Moorman; Romagnoli, Romeo; Preti, Delia; Baraldi, Stefania; Ruggiero, Emanuela; Varani, Katia; Targa, Martina; Vincenzi, Fabrizio; Borea, Pier Andrea; AGHAZADEH TABRIZI, Mojgan
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/1683528
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