6-Methoxy-N-alkyl Isatin Acylhydrazone Derivatives as a Novel Series of Potent Selective Cannabinoid Receptor 2 Inverse Agonists: Design, Synthesis, and Binding Mode Prediction

DIAZ, PHILIPPE; PHATAK, SHARANGDHAR S.; XU, J.; DIAZ, FANNY-ASTRUC; CAVASOTTO, CLAUDIO N.; NAGUIB, MOHAMMED

JOURNAL OF MEDICINAL CHEMISTRY

AMER CHEMICAL SOC

Año: 2009 vol. 52 p. 433 - 444

0022-2623

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.