Modification And Structure-activity Relationship Research Of ZL006

Nitric oxide(NO)is an inorganic free radical gas that is involved in a wide range of physiological functions and pathophysiological states.NO is produced by a family of three heme binding enzymes called nitric oxide synthase(NOS).Neuronal or brain NOS(nNOS or NOS1)is constitutively expressed and thought to play a role in neurotransmission and smooth muscle relaxation,respectively.Inthe nervous system NMDAR/PSD-95/nNOS pathways is an key factor in the synthesize of NO.A novel approach to selectively inhibit the NMDAR/PSD-95/nNOS signaling pathway is to disrupt the nNOS/PSD-95 interaction.This would allow for specific inhibition of the NMDAR-nNOS signaling pathway,without blocking NMDAR dependent,but nNOS-independent signaling pathway,thereby sparing unwanted effect on many other important physiological progresses mediated by the NMDA receptor.The previous research of our lab synthesized PSD-95/nNOS uncoupling activity of compound ZL006,which have neuroprotective activity.In this thesis,on the basis of the some previous syntheses target compounds structure-activity relationships analysis,through modifying the ZL006 hydrophobic end volume,hydrophobic and hydrophilic end connections,the hydrophilic end into the lipophilic group,synthetic prodrug,twin drug structurewe designed and synthesized 26 new compounds.The structures of those compounds were identified by ~1HNMR,and those compounds are novel compounds,that were not reported in the literature.Thecompounds pharmacologically active analysis suggest that1)Modificating the methylene of ZL006 which bond hydrophilic and hydrophobic end.Introducing the lipophilic group can prolong the action time,relief of target;Replacing secondary amine connectionby amide connections have neuroprotective activity suggest that molecular connection mode need to further structure modification.2)Changing benzene ring of ZL006 to naphthalene ring still have neuroprotective activity,to pyridine ring without any activity,showed thata certain volume hydrophobic endbinding to targets"pocket domain"is structure activity group.3)The chlorine atom ZL006 hydrophobic end hydroxyl vicinal into bromine atom,results in decreased compound neuroprotective activity,has proved ortho hydroxy group should not introduced bulky groups.4)Reducing hydrophilic of ZL006 can result in decreased activity.5)Synthesize ZL006 and GABA those has the analgesic activity to twin drug,pharmacological result shows twin drug haveneuroprotective effect,the idea for its analgesic activity still need to be further validated by animal experiment.In summary,we get new QSAR:molecular hydrophobic end volume too small has no activity;5',6'increased volume will increased activity;changing connection of molecular can keep activity,we can make further structure modification;drawing lipophilic group into hydrophilic end decreased the active so if replacing lipophilic group by hydrophilic group maybe make activity increase.