Producción CyT
Artículo
Autoría
DIAZ, PHILIPPE
;
PHATAK, SHARANGDHAR S.
;
XU, J.
;
DIAZ, FANNY-ASTRUC
;
CAVASOTTO, CLAUDIO NORBERTO
;
NAGUIB, MOHAMMED
Fecha
2009
Editorial y Lugar de Edición
AMER CHEMICAL SOC
Revista
JOURNAL OF MEDICINAL CHEMISTRY,
vol. 52
(pp. 433-444)
AMER CHEMICAL SOC
Resumen
Información suministrada por el agente en
SIGEVA
Recently, we discovered and reported a series of N-alkyl isatin acylhydrazone derivatives that are potent CB2 agonists. Here, we describe a novel series of selective CB2 inverse agonists resulting from introduction of a methoxy moiety in position 6 of the isatin scaffold. These novel 6-methoxy-N-alkyl isatin acylhydrazone derivatives exhibited high CB2 functional activity and selectivity at human CB2. Compound 16 (MDA77) had high activity (EC50 = 5.82 nM) at CB2 and no activity at CB1. Compound...
Recently, we discovered and reported a series of N-alkyl isatin acylhydrazone derivatives that are potent CB2 agonists. Here, we describe a novel series of selective CB2 inverse agonists resulting from introduction of a methoxy moiety in position 6 of the isatin scaffold. These novel 6-methoxy-N-alkyl isatin acylhydrazone derivatives exhibited high CB2 functional activity and selectivity at human CB2. Compound 16 (MDA77) had high activity (EC50 = 5.82 nM) at CB2 and no activity at CB1. Compound 15 (MDA55) (Ki = 89.9 nM, EC50 = 88.2 nM at CB2) inhibited the effect of compound 1 (MDA7), a selective CB2 agonist, in an animal model of neuropathic pain. The molecular modeling study presented here represents a first study of CB2 based on the structure of beta2-adrenergic receptor. A ligand-based homology model of the CB2 binding site was developed, and on the basis of our results, we propose a general binding mode for this class of inverse agonists with CB2.
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Palabras Clave
ANTAGONISTSCANNABINOID RECEPTOR 2LIGAND-STEERED MODELINGISATIN DERIVATIVES