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.
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 (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 beta(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.
Diaz
Philippe
P
Department of Anesthesiology and Pain Medicine, Unit 409, The University of Texas M. D. Anderson Cancer Center, 1400 Holcombe Boulevard, Houston, Texas 77030, USA.
Phatak
Sharangdhar S
SS
Xu
Jijun
J
Astruc-Diaz
Fanny
F
Cavasotto
Claudio N
CN
Naguib
Mohamed
M
D018360:Crystallography, X-Ray; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006860:Hydrogen Bonding; D007510:Isatin / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism
D006835:Hydrazones; D043885:Receptor, Cannabinoid, CB2; D007510:Isatin