Design And Synthesis Of Novel Neuropathic Pain Drugs

Neuropathic pain is directly caused by disease or injury of the somatic sensory nervous system which was defined as one kind of chronic pains including painful diabetic neuropathy,trigeminal neuralgia,sciatica and pain of spinal cord injury.At present,the pathogenesis of neuropathic pain is not crystal clear.Furthermore,there is no satisfactory treatment to this disease.N-methyl-D-aspartate receptor(NMDA)play a very important role in the process of peripheral tissue injury or nerve injury-induced hypersensitivity.The study showes that the NMDAR antagonists produced specific anti-neuralgia effects.However the wide distribution in the central nervous system as well as the extensive physiological function have limited the application of NMDAR as analgesic agents in clinic.Inhibitors of the PSD95-nNOS interaction specifically block NMDAR signalling coupled to nNOS without affecting the physiological function of the NMDAR and nNOS that will reduce the release of NO and the injury of neuronal.ZL006,an inhibitors of the PSD95-nNOS interaction is synthesized by our lab which can demonstrate action only by intravenous injection or intrathecal injection.Its poor Oral effect,short half-time and low penetration to blood brain barrier suggest that we need do something to improve its drugability.Base on the structure activity relationships of ZL006 studied through preliminary research,we carried out the drug design as follows:combine its carboxyl group with GABAa receptor agonist by ester bond to give synergistic effect;chose substituents with large steric hindrance on hydrophobic ends to enhance the pharmacal effect;modify the hydrophilic end structure to enhance water solubility and bioavailability.17 target compounds have been designed and synthesized and their structures were confirmed by 1H-NMR and MS.The pharmacological experiment result showed that some target compounds provided excellent analgesic activity and the solubility of some compounds were improved which were measured by HPLC.These studies will surely shed new light on the prevention and treatment of neuropathic pain.