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

Abstract

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.

Borolatonin limits cognitive deficit and neuron loss while increasing proBDNF in ovariectomised rats

“…Melatonin (B6768) as well as borolatonin precursors were purchased from Sigma-Aldrich Co. (St. Louis, MO, USA). The synthesis of borolatonin agreed with previously reported methods [23].…”

“…However, no changes in neuronal survival were observed. Similar results were observed after the equimolar administration of melatonin [23]. Some of these changes could be related to reported positive effects of melatonin administration in the cholinergic system, among these are: Inhibition of the calcium-induced release of acetylcholinesterase, promotion of choline transport improving acetylcholine synthesis, rescue of acetylcholine transferase activity in the frontal cortex and hippocampus [13]; but further experiments are required to support these effects by borolatonin administration.…”

“…Any mechanisms of action (which to the best of our knowledge is unclarified today) for these compounds in cognitive deficit observed after castration appear to be shared [49], while the structural relationship supports the involvement of melatonin receptors in playing a key role in modulating memory processes [52, 53]. Further studies are required to measure the ability and mechanism(s) of borolatonin to cross the blood–brain barrier (albeit if several changes in behavior and brain suggest its ability) [23], and the affinity of borolatonin on melatonin receptors, or on other receptors; if the latter is the case, also the selectivity of borolatonin on a specific receptor must be determined.…”

“…That could be involved in the sex and gender differences of incidence in some neurodegenerative diseases, specifically in the oestrogens-AD relationship [28]. Thus, in this work, the behavioral evaluation and immunohistopathologic analysis of brain samples from female rats treated with borolatonin (a compound among BCC with presumptive application in brain disorders [23,30]) was carried out. Furthermore, due to the relevance of amyloid limitation as the mechanism of action linked to the effectiveness of AD agents, the effects of the administration of borolatonin to cells with induced Aβ-toxicity were determined in vitro.…”

Beneficial Effect of Melatonin Alone or in Combination with Glatiramer Acetate and Interferon β-1b on Experimental Autoimmune Encephalomyelitis

“…In addition, melatonin does not have a toxic effect even when used in very high doses and for a long time, and it is well assimilated [21]. Exogenous melatonin has neuroprotective actions in several animal models [22,23]. These findings highlight the use of exogenous melatonin as an adjuvant therapy for degenerative diseases.…”