In this review we summarized the actual clinical data for a cardioprotective therapeutic role of melatonin, listed melatonin and its agonists in different stages of development, and evaluated the melatonin cardiovascular target tractability and prediction using machine learning on ChEMBL. To date, most clinical trials investigating a cardioprotective therapeutic role of melatonin are in phase 2a. Selective melatonin receptor agonists Tasimelteon, Ramelteon, and combined melatonergic-serotonin Agomelatine, and other agonists with registered structures in CHEMBL were not yet investigated as cardioprotective or cardiovascular drugs. As drug-able for these therapeutic targets, melatonin receptor agonists have the benefit over melatonin of well-characterized pharmacologic profiles and extensive safety data. Recent reports of the X-ray crystal structures of MT1 and MT2 receptors shall lead to the development of highly selective melatonin receptor agonists. Predictive models using machine learning could help to identify cardiovascular targets for melatonin. Selecting ChEMBL scores > 4.5 in cardiovascular assays, and melatonin scores > 4, we obtained 284 records from 162 cardiovascular assays carried out with 80 molecules with predicted or measured melatonin activity. Melatonin activities (agonistic or antagonistic) found in these experimental cardiovascular assays and models include arrhythmias, coronary and large vessel contractility, and hypertension. Preclinical proof-of-concept and early clinical studies (phase 2a) suggest a cardioprotective benefit from melatonin in various heart diseases. However, larger phase 3 randomized interventional studies are necessary to establish melatonin and its agonists’ actions as cardioprotective therapeutic agents.
By replacing a phenolic
ring of (
E
)-resveratrol
with an 1,3,4-oxadiazol-2(3
H
)-one heterocycle, new
resveratrol-based multitarget-directed ligands (MTDLs) were obtained.
They were evaluated in several assays related to oxidative stress
and inflammation (monoamine oxidases, nuclear erythroid 2-related
factor, quinone reductase-2, and oxygen radical trapping) and then
in experiments of increasing complexity (neurogenic properties and
neuroprotection
vs
okadaic acid). 5-[(
E
)-2-(4-Methoxyphenyl)ethenyl]-3-(prop-2-yn-1-yl)-1,3,4-oxadiazol-2(3
H
)-one (
4e
) showed a well-balanced MTDL profile:
cellular activation of the NRF2-ARE pathway (CD = 9.83 μM),
selective inhibition of both hMAO-B and QR2 (IC
50
s = 8.05
and 0.57 μM), and the best ability to promote hippocampal neurogenesis.
It showed a good drug-like profile (positive in vitro central nervous
system permeability, good physiological solubility, no glutathione
conjugation, and lack of PAINS or Lipinski alerts) and exerted neuroprotective
and antioxidant actions in both acute and chronic Alzheimer models
using hippocampal tissues. Thus,
4e
is an interesting
MTDL that could stimulate defensive and regenerative pathways and
block early events in neurodegenerative cascades.
Gamma- and delta-isomers of hexachlorocyclohexane caused marked decreases in the levels of radioactive phospholipids, and increases in the levels of [3H]arachidonate incorporated into free fatty acids in rat renal tubular cells. The increased radioactivity of free fatty acids arises from the decrease of [3H]arachidonate incorporated into phosphatidylinositol, but not into phosphatidylcholine, phosphatidylserine or phosphatidylethanolamine. This fact suggests that phosphatidylinositol can be broken down to the fatty acid from the sn-2 position and lysophospholipid by a phospholipase activity increased by hexachlorocyclohexanes. The observed specific toxicant action could be achieved in two ways: (a) operating upon a specific phospholipase A2 that acts on phosphatidylinositol, but not on other phospholipids as substrates and/or (b) involving substrate-phospholipase A2 interactions. Interestingly, the observed effect of the delta-isomer was more pronounced than that of the gamma-one.
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