Monoamines and their Derivatives on GPCRs: Potential Therapy for Alzheimer’s Disease

Abstract

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.

Drug-Targeted Genomes: Mutability of Ion Channels and GPCRs

“…Next, the matching rate of one of the two factors with druggable GPCRs (Figure 3a) was reminiscent of the result obtained from Alzheimer's disease (AD) and monogenic hypertension (MH), which resulted in the matches of either of the two factors and the disease at ~84% (59 of 70 genes susceptible to AD; 66 of 79 genes causative of MH) [69,70]. Indeed, GPCRs become important targets in understanding the molecular mechanisms underlying AD [144][145][146][147][148] and hypertension [134][135][136][137][138][139][140][141][142][143]. Inconsistent with the prior reports [69,70], however, there was an atypical significant relationship in proximity to telomeres with respect to the molecular size (FL) of the druggable GPCRs (Figure 3b,c).…”

Synthesis, In Silico, and Biological Evaluation of a Borinic Tryptophan-Derivative That Induces Melatonin-like Amelioration of Cognitive Deficit in Male Rat

“…These shorter latencies are related to the decreased levels of androgens in rats [ 35 ] and are in line with memory disruption related to androgens decreasing in humans [ 36 , 37 ]. In rats, steroid decreasing causes effects in the synthesis and degradation of key neurotransmitters such as acetylcholine, catecholamines, and other monoamines [ 8 , 38 , 39 ], including melatonin [ 38 , 39 ].…”

“…Furthermore, melatonin induces beneficial effects on the cholinergic system by increasing acetylcholine release and inhibiting choline acetyltransferase [ 7 ]. Furthermore, it also appears to exert benefits linked to the modulation of other monoamine systems, such as the serotonergic and dopaminergic systems by means of unestablished mechanisms [ 7 , 8 ].…”

“…Additionally, the chemical structure of melatonin is related to structures acting as antioxidants or regulators of inflammation [ 9 , 10 ]; in fact, its administration limits the excessive influx of Ca 2+ and the excessive efflux of Mg 2+ related to some inflammatory and neurotoxicity mechanisms [ 7 , 8 ].…”

Inhibition of Astrocytic Histamine N-Methyltransferase as a Possible Target for the Treatment of Alzheimer’s Disease

“…Several studies of post-mortem AD brains have shown changes in monoamine transmitter systems including serotonin [6], noradrenalin [7], histamine [8], and ACh [35] which tend to show early and severe damage. Low monoamine levels have been found, which precede the loss of its producing neurons [36]. For this reason, significant efforts have been made to determine the relationship between neurotransmitters dysfunction and AD pathogenesis [37].…”