6-methoxy-VV-alkyl isatin acylhydrazone derivatives as a novel series of potent selective cannabinoid receptor 2 inverse agonists: Design, synthesis, and binding mode prediction

Philippe Diaz, Sharangdhar S. Phatak, Jijun Xu, Fanny Astruc-Diaz, Claudio N. Cavasotto, Mohamed Naguib

Research output: Contribution to journalArticlepeer-review

Abstract

Recently, we discovered and reported a series of VV-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-VV-alkyl isatin acylhydrazone derivatives exhibited high CB2 functional activity and selectivity at human CB2. Compound 16 (MDA77) had high activity (EC 50 = 5.82 nM) at CB2 and no activity at CB1. Compound 15 (MDA55) (K i = 89.9 nM, EC 50 = 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 β 2-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.

Original languageEnglish
Pages (from-to)433-444
Number of pages12
JournalJournal of Medicinal Chemistry
Volume52
Issue number2
DOIs
StatePublished - Jan 22 2009

Fingerprint

Dive into the research topics of '6-methoxy-VV-alkyl isatin acylhydrazone derivatives as a novel series of potent selective cannabinoid receptor 2 inverse agonists: Design, synthesis, and binding mode prediction'. Together they form a unique fingerprint.

Cite this