Studies On Design, Synthesis And Biological Activity Of Agmatine Derivatives

In this paper, advances in research on the mechanisms of opioid addiction and the targets of anti-opioid dependence were reviewed. A variety of useful bioactivities (including modulation on opioid functions, analgesic, cancer chemopreventive, neuroprotective, antidepressive) of agmatine and the mechanisms were also summarized in the dissertation.Agmatine is an endogenous substance in human being, it can enhance opioid analgesia and inhibit tolerance to and substance dependence on opioids. It suggest that agmatine might be developed for treatment of opioid tolerance and dependence. Agmatine is of low toxicity, but the pharmacokinetic properties of agmatine restrict its drug use, such as not easy to cross blood-brain barrier and fast excretion.Lipophilicity is an essential feature for the penetration of a molecule through the blood-brain barrier, so we designed some structurally-related agmatine derivatives with better lipophilicity (substituting guanidine with 2-nitroethene-1,1-diamine or N-cyanoguanidine). Since there are several targets related to agmatine modulation on opioid functions, we also consider to improve the structure diversity of designed compounds.In this thesis, 54 derivatives of agmatine have been designed and synthesized, 45 of them have not been reported in literatures. These compounds are divided into three different categories: N,N'-disubstituted-2-nitroethene-l,l-diamine derivatives (25 compounds); N,N'-disubstituted-N"-cyanoguanidine derivatives (24 compounds); substituted guanidine derivatives(5 compounds). Their structures were confirmed by NMR, MS and element analysis.Three isotopic labelled agmatine were synthesized, the tritium labelled agmatine was obtained with a specific activity of 40 Ci/mmol and a radiochemical purity of 95%. The 2 deuterium labeled agmatine were obtained with a isotopic purity of 98.6% and 90%. These isotopic labelled agmatine is with sufficient purity for its pharmacokinetic studies.The calcium channel block and neuroprotective effect of agmatine and 13 analogues were evaluated. The result showed that most compound can fully block the calcium channel at 100μM. And the neuroprotective rate of most compounds is more than 80％at 10μM, 3 compounds can reach 95％even at 1μM.Agmatine has weak analgesic effect and might with the similar mechanism of its effect on enhance opioid analgesia, but inhibit tolerance to and substance dependence on opioids. The analgesic activity was evaluated with acetic acid-induced writhing in mice, the compound was inject hypodermically at a dose of 30mg/kg or administered orally at a dose of 40mg/kg. The activity of compounds N01, N05, N06, Q02, Q04, Q05, Q12 and Q14 are comparable to agmatine.Most synthesized compounds showed improved BBB permeation profile and part of them can cross the BBB predicted by Volsurf.Two compounds was seleceted (with good analgesic activity and BBB permeation profile) and their effect on enhancing opioid analgesia was evaluated. The compounds was administered orally at a dose of 40mg/kg, and both compounds showed remarkable effect on enhance opioid analgesia. Agmatine can decreased the analgesic EDs0 of morphine by 40％, the two compounds is 31.6％and 29.2％, respectively.The structure-activity relationship between these compounds and their analgesic activity, BBB permeation profile were discussed.In conclusion, some derivatives and analogues shows notable effect of analgesic, neuroprotective and enhance opioid analgesia, and these would be helpful for further studies in this filed.