| Among the various mental illnesses,depression is a very common and serious illness,which could even lead to suicide and bring heavy economic burden to society and individual.Melatonin(MT)receptor and 5-hydroxy-tryptamine(5-HT)receptor were involved in mediating numerous brain functions and central nervous system diseases and closely related to depression.The current pharmacological prevention and treatment of depression include fluoxetine,paroxetine,sertraline,fluvoxamine,citalopram,venlafaxine and so on.Although antidepressants play a significant therapeutic action clinically,there are also shortcomings,development of novel classes of antidepressant drugs with high-efficiency and low-toxicity is still needed.Natural small molecules with multifarious molecular skeleton and particular activities are fascinating sources for drug discovery.In order to find active molecules with antipsychotic effects,our random screening indicated that tropine,gramine and thymol,natural small molecules,exhibited moderate agonistic activities on MT and 5-HT receptors.To increase agonistic activities and study structure-activity relationships,ninety-seven derivatives of tropine,thymol and gramine were synthesized for developing new MT and 5-HT receptors agonists.Meanwhile,their preliminary structure-activity relationships(SARs)were also discussed.The natural tropane alkaloids with interesting bicyclic scaffolds aroused great attention for their diverse activities to provide tremendous opportunities for novel drugs discovery,however,their agonistic effects on MT1 and MT2 receptors have not been reported.Our previous studies proposed that tropine exhibited agonistic activities on MT1 and MT2 receptors with agitating rates of 90.50%and 77.48%at the concentration of 1mM.Thus,bioassay-guided synthesis led to forty-six derivatives of tropine as new MT1 and MT2 receptors agonists.Fifteen compounds were found to be active on MT1 receptor,and ten compounds with high agonistic activities on MT1 and MT2 receptors were worth further studying.Derivatives 8,14 and 20 had better agonistic activities with EC50 values of 0.33,0.23 and 0.20 mM on MT1 receptor,and 0.38,0.28 and 0.24 mM on MT2 receptor,respectively.Our previous screening revealed that gramine exhibited activities on MT1 and 5-HT1A receptors with agitating rates of 182.12%and 136.45%at the concentration of 1mM.Twenty-six derivatives were synthesized by the chemical modification at N-1 and N-1' position,and evaluated for their agonist activities.The study showed that some of the tested compounds demonstrated a dose-dependent manner on MT1 and 5-HT1A receptors.Among them,derivatives(53,67 and 69)owned similar agonistic rates on MT1 receptor,and ten derivates(49,50,51,53,54,62,63,67,68 and 70)had relatively stronger agonisting effect on 5-HT1A receptor.Interestingly,derivatives(53,67 and 69)simultaneously exhibited significant agonistic activities on two receptors with EC50 values of 0.51,0.39,0.50 mM(on MT1 receptor)and 0.28,0.46,0.23 mM(on 5-HT1A receptor),respectively.Thymol possessed significant activities on MT1,MT2,5-HT1A and 5-HT2C receptors with agitating rates of 134.63%,202.12%,64.14%and 89.76%at the concentration of 1mM by our previous screening.Thus,twenty-five derivatives were synthesized by steglich esterification,etherification,formylation,acetylation,glycosylation reaction,and evaluated for their agonist activities.Disappointedly,the tested results showed that the activities of derivatives decreased.The review summarized 209 natural tropane alkaloids,and expounded different types and biological activities of these tropane alkaloids.Modern pharmacological study proposed that tropane alkaloids had central nervous system,glycosidic enzyme inhibition,drug resistance reversal,antioxidant activities and so on,which provides a reference for further research and application of tropane alkaloids. |
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