Albeit cholinergic depletion remains the key event in Alzheimer’s Disease (AD), recent information describes stronger links between monoamines (trace amines, catecholamines, histamine, serotonin, and melatonin) and AD than those known in the past century. Therefore, new drug design strategies focus efforts to translate the scope on these topics and to offer new drugs which can be applied as therapeutic tools in AD. In the present work, we reviewed the state-of-art regarding genetic, neuropathology and neurochemistry of AD involving monoamine systems. Then, we compiled the effects of monoamines found in the brain of mammals as well as the reported effects of their derivatives and some structure-activity relationships. Recent derivatives have triggered exciting effects and pharmacokinetic properties in both murine models and humans. In some cases, the mechanism of action is clear, essentially through the interaction on G-protein-coupled receptors as revised in this manuscript. Additional mechanisms are inhibition of enzymes for their biotransformation, regulation of free-radicals in the central nervous system and others for the effects on Tau phosphorylation or amyloid-beta accumulation. All these data make the monoamines and their derivatives attractive potential elements for AD therapy.

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Preclinical and clinical evidence supports melatonin and its analogues as potential treatment for diseases involving cognitive deficit such as Alzheimer’s disease. In this work, we evaluated by in silico studies a set of boron-containing melatonin analogues on MT1 and MT2 receptors. Then, we synthesized a compound (borolatonin) identified as potent agonist. After chemical characterization, its evaluation in a rat model with cognitive deficit showed that it induced ameliorative effects such as those induced by equimolar administration of melatonin in behavioral tests and in neuronal immunohistochemistry assays. Our results suggest the observed effects are by means of action on the melatonin system. Further studies are required to clarify the mechanism(s) of action, as the beneficial effects on disturbed memory by gonadectomy in male rats are attractive.

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