Design And Synthesis Of Dual-target Drugs Based On PSD95-nNOS Uncouplers

In recent years,N-methyl-D-aspartate(NMDA)receptor antagonists have been widely used in the treatment of central nervous system diseases,including stroke,pain and depression.However,the widespread and functional distribution of NMDA receptors in the central nervous system limits its clinical application.The activation of NMDA receptors leads to a large influx of Ca2+and through the postsynaptic density protein 95(PSD95)mediated regulating activation of downstream of nitric oxide synthase(nNOS),to form NMDAR-PSD95-nNOS signaling Molecular complexes.Studies have shown that this signaling pathway is associated with multiple central nervous system diseases such as stroke,pain and depression.The PSD95-nNOS uncoupling agent was applied to the downstream of the NMDAR-PSD95-nNOS signaling pathway,which does not affect the normal physiological functions of NMDAR and nNOS,has attracted wide attention.HDACs inhibitors were first used in the treatment of tumors.In recent years,a large number of studies have found that HDACs play an important role in the development of the nervous system and are important regulators of neuronal differentiation,survival and maturation.HDACs inhibitors act on multiple pathological aspects of ischemic stroke,such as excitotoxicity,oxidative stress,inflammatory response,apoptosis and regeneration of nerve cells,suggesting that HDACs is a new target for a potential in the treatment of ischemic stroke.The small molecule compound ZL006 synthesized by our research group has good PSD95-nNOS uncoupling activity,and it has good therapeutic activity for stroke and neuropathic pain.However,ZL006 has some disadvantages,such as poor oral effect,difficult to penetrate the blood-brain barrier,short half-life,poor drug quality and so on.Based on ZL006’s structure-activity relationship,this paper makes the following design:hydrophilic introduction of the pharmacophore of benzohydroxamic acid HDACs inhibitor;chose substituents with large steric hindrance on hydrophobic ends to enhance the pharmacal effect.It is expected to be able to get better multi-target drugs in the anti-stroke therapy.The ZL006-05,a compound of ZL006 combined with GABA receptor agonist borneol,has been found to have good therapeutic activity for stroke and neuropathic pain.Because of the shortcomings of water solubility and bioavailability of ZL006-05,this paper designs the introduction of glycine in its structure to enhance water solubility and bioavailability.Expect to improve the shortcomings of ZL006-05.