39 research outputs found
Metabolic benefits of 1-(3-(4-(o-tolyl)piperazin-1-yl)propyl)pyrrolidin-2-one : a non-selective α-adrenoceptor antagonist
Purpose Previous studies have shown that several components
of the metabolic syndrome, such as hypertension,
obesity or imbalanced lipid and carbohydrate homeostasis,
are associated with the sympathetic nervous system overactivity.
Therefore, the inhibition of the adrenergic nervous
system seems to be a reasonable and appropriate therapeutic
approach for the treatment of metabolic disturbances. It
has been suggested that non-selective adrenoceptor antagonists
could be particularly beneficial, since 1-adrenoceptor
antagonists can improve disrupted lipid and carbohydrate
profiles, while the inhibition of the 2-adrenoceptor may
contribute to body weight reduction. The aim of the present
study was to investigate the metabolic benefits deriving
from administration of a non-selective -adrenoceptor
antagonist from the group of pyrrolidin-2-one derivatives.
The aim of the present study was to investigate the potential
metabolic benefits deriving from chronic administration o a non-selective -adrenoceptor antagonist, from the group
of pyrrolidin-2-one derivatives.
Methods The 1- and 2-adrenoreceptor affinities of the
tested compound-1-(3-(4-(o-tolyl)piperazin-1-yl)propyl)
pyrrolidin-2-one had been investigated previously by means
of the radioligand binding assay. In the present study, we
extended the pharmacological profile characteristics of the
selected molecule by additional intrinistic activity assays.
Next, we investigated the influence of the tested compound
on body weight, hyperglycemia, hypertriglyceridemia, blood
pressure in the animal model of obesity induced by a highfat
diet, and additionally we measured the spontaneous activity
and body temperature.
Results The intrinistic activity studies revealed that the
tested compound is a potent, non-selective antagonist of
1B and 2A-adrenoceptors. After the chronic administration
of the tested compound, we observed reduced level of
triglycerides and glucose in the rat plasma. Interestingly, the
tested did not reduce the body weight and did not influence
the blood pressure in normotensive animals. Additionally,
the administration of the tested compound did not change the
animals' spontaneous activity and body temperature.
Conclusion Non-selective -adrenoceptor antagonist
seems to carry potential benefits in the improvement of the
reduction of elevated glucose and triglyceride level. The lack
of influence on blood pressure suggests that compounds with
such a pharmacological profile may be particulary beneficial
for the patients with disturbed lipid and carbohydrate
profile, who do not suffer from hypertension. These results
are particulary valuable, since currently there are no safe
2A-adrenoceptor antagonist drugs available in clinical use
with the ability to modulate hyperglycemia that would not
affect blood pressure
Naturally Inspired Molecules for Neuropathic Pain Inhibition—Effect of Mirogabalin and Cebranopadol on Mechanical and Thermal Nociceptive Threshold in Mice
Background: Neuropathic pain is drug-resistant to available analgesics and therefore novel treatment options for this debilitating clinical condition are urgently needed. Recently, two drug candidates, namely mirogabalin and cebranopadol have become a subject of interest because of their potential utility as analgesics for chronic pain treatment. However, they have not been investigated thoroughly in some types of neuropathic pain, both in humans and experimental animals. Methods: This study used the von Frey test, the hot plate test and the two-plate thermal place preference test supported by image analysis and machine learning to assess the effect of intraperitoneal mirogabalin and subcutaneous cebranopadol on mechanical and thermal nociceptive threshold in mouse models of neuropathic pain induced by streptozotocin, paclitaxel and oxaliplatin. Results: Mirogabalin and cebranopadol effectively attenuated tactile allodynia in models of neuropathic pain induced by streptozotocin and paclitaxel. Cebranopadol was more effective than mirogabalin in this respect. Both drugs also elevated the heat nociceptive threshold in mice. In the oxaliplatin model, cebranopadol and mirogabalin reduced cold-exacerbated pain. Conclusions: Since mirogabalin and cebranopadol are effective in animal models of neuropathic pain, they seem to be promising novel therapies for various types of neuropathic pain in patients, in particular those who are resistant to available analgesics
The antiarrhythmic activity of novel pyrrolidin-2-one derivative S-75 in adrenaline-induced arrhythmia
Arrhythmia is a quivering or irregular heartbeat that can often lead to blood clots, stroke, heart failure, and other heart-related complications. The limited efficacy and safety of antiarrhythmic drugs require the design of new compounds. Previous research indicated that pyrrolidin-2-one derivatives possess an affinity for α1-adrenergic receptors. The blockade of α1-adrenoceptor may play a role in restoring normal sinus rhythm; therefore, we aimed to verify the antiarrhythmic activity of novel pyrrolidin-2-one derivative S-75. In this study, we assessed the influence on sodium, calcium, potassium channels, and β1-adrenergic receptors to investigate the mechanism of action of S-75. Lack of affinity for β1-adrenoceptors and weak effects on ion channels decreased the role of these adrenoceptors and channels in the pharmacological activity of S-75. Next, we evaluated the influence of S-75 on normal ECG in rats and isolated rat hearts, and the tested derivative did not prolong the QTc interval, which may confirm the lack of the proarrhythmic potential. We tested antiarrhythmic activity in adrenaline-, aconitine- and calcium chloride-induced arrhythmia models in rats. The studied compound showed prophylactic antiarrhythmic activity in the adrenaline-induced arrhythmia, but no significant activity in the model of aconitine- or calcium chloride-induced arrhythmia. In addition, S-75 was not active in the model of post-reperfusion arrhythmias of the isolated rat hearts. Conversely, the compound showed therapeutic antiarrhythmic properties in adrenaline-induced arrhythmia, reducing post-arrhythmogen heart rhythm disorders, and decreasing animal mortality. Thus, we suggest that the blockade of α1-adrenoceptor might be beneficial in restoring normal heart rhythm in adrenaline-induced arrhythmia