TY - JOUR
T1 - 6-methoxy-VV-alkyl isatin acylhydrazone derivatives as a novel series of potent selective cannabinoid receptor 2 inverse agonists
T2 - Design, synthesis, and binding mode prediction
AU - Diaz, Philippe
AU - Phatak, Sharangdhar S.
AU - Xu, Jijun
AU - Astruc-Diaz, Fanny
AU - Cavasotto, Claudio N.
AU - Naguib, Mohamed
PY - 2009/1/22
Y1 - 2009/1/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=60549101109&partnerID=8YFLogxK
U2 - 10.1021/jm801353p
DO - 10.1021/jm801353p
M3 - Article
C2 - 19115816
AN - SCOPUS:60549101109
SN - 0022-2623
VL - 52
SP - 433
EP - 444
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 2
ER -