Design,Synthesis,and Biological Activity Of Indole Carboxamide CB2 Receptor Agonists

The Cannabinoid Receptor?CB?is a receptor in the large family of G protein-coupled receptors and is specifically classified into two types,CB1 and CB2.CB2receptors are mainly distributed in the immune cells of peripheral nerve tissues,and its signal pathways,such as adenylate cyclase and phospholipase C,are associated with various diseases.Nabiximols,a non-selective CB2 receptor agonist,has been used in25 countries to treat multiple sclerosis,and its clinical side effects may be related to CB1 receptors acting on the central nervous system.This dissertation selected a class of indole carboxamide CB2 receptor agonist abused drug SDB-001(EC_50,CB1=34 nM,EC_50,CB2=29 nM)which has recently shown a potent cannabimimetic effect in rats.In order to obtain selective CB2 receptor agonists,it was structurally modified by two strategies.Strategy I:Selecting a functional group that is active on CB2 receptors,and modifying the structure of the non-selective or poorly selective cannabinoid receptor agonist,thereby increasing the selectivity of the compound for the CB2 receptor;Strategy II:introducing polar groups to the benzene ring region of the indole for reducing the permeability of the blood-brain barrier for compounds,thereby blocking the binding of the compound and CB1 receptors distributed in the central nervous system.The main innovations of this paper are reflected in the following aspects:1)A series of highly selective carboxamide CB2 receptor agonists have been developedThis dissertation aims at newly discovered indole CB2 receptor agonist abused drug SDB-001,which has a powerful cannabimimetic effect in rats,by selecting a dominant group that is favorable for CB2 receptor activity and introducing a polar group which is in order to reduce the blood brain barrier permeability of the compound.Finally,a class of highly selective CB2 receptor agonists was obtained.2)Selective CB2 Receptor Agonist 3-33 can significantly relieve clinical symptoms in an experimental autoimmune encephalomyelitis model of mice with multiple sclerosis.Compound 3-33 was pharmacokinetically tested in mice by intraperitoneal injection and had a high plasma exposure.Compound 3-33 can effectively alleviate the clinical symptoms in mouse experimental autoimmune encephalomyelitis model for multiple sclerosis.Through histopathological analysis,it was found that it can significantly reduce the degree of demyelination in a mouse experimental autoimmune encephalomyelitis model.3)Minor structural changes to CB2 receptor ligands can turn agonists into antagonistsWhen the CB2 receptor agonists 2-4?EC50,CB2=59 nM?were introduced into methoxy and methylthio group at the C-7 position,the CB2 receptor antagonists 2-32?IC50,CB2=16 nM?and 2-41?IC50,CB2=28 nM?were obtained which achieved the transition from agonist to antagonist.The phenyl side chain of residue F117 and the aromatic side chain of residue W258 transform from parallel?-?interactions to T-type?-?interactions is the key to the conversion of agonists into antagonists by Molecular dynamics simulation.In this dissertation,a series of indole carboxamide CB2 receptor agonists wereobtained by rational medicinal chemistry design and their structure-activity relationships were studied.Compound 3-33 has a high plasma exposure in mice,and it can significantly alleviate the clinical symptoms in multiple sclerosis mice experimental autoimmune encephalomyelitis models,which provides support for the selective CB2 receptor agonist for treatment of multiple sclerosis.