Abstract
PurposePrevious 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 α1-adrenoceptor antagonists can improve disrupted lipid and carbohydrate profiles, while the inhibition of the α2-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 α-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 of a non-selective α-adrenoceptor antagonist, from the group of pyrrolidin-2-one derivatives.MethodsThe α1- and α2-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 high-fat diet, and additionally we measured the spontaneous activity and body temperature.ResultsThe intrinistic activity studies revealed that the tested compound is a potent, non-selective antagonist of α1B and α2A-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.ConclusionNon-selective α-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 α2A-adrenoceptor antagonist drugs available in clinical use with the ability to modulate hyperglycemia that would not affect blood pressure.
Highlights
The metabolic syndrome has been defined as a simultaneous occurrence of at least three out of five symptoms, such as impaired fasting glycaemia, abdominal obesity, elevated blood pressure, hypertriglyceridemia, and low levels of high density lipoprotein (HDL) [1]
We investigated the effect of the non-selective α-adrenoceptor antagonist; 1-(3-(4-(o-tolyl) piperazin-1-yl)propyl)pyrrolidin-2-one (EP-47) on the body weight, hyperglycemia, hypertriglyceridemia, spontaneous activity in animals with obesity induced by a high-fat diet, as well as blood pressure and temperature
We have identified a series of pyrrolidin2-one derivatives bearing an arylpiperazine fragment, which exerted a strong binding to α-adrenoceptors [22]
Summary
The metabolic syndrome has been defined as a simultaneous occurrence of at least three out of five symptoms, such as impaired fasting glycaemia, abdominal obesity, elevated blood pressure, hypertriglyceridemia, and low levels of high density lipoprotein (HDL) [1]. Recent statistic reports have shown that the metabolic syndrome occurs in 20-25% of the adult population, and it has already reached epidemic proportions [2]. It constitutes a serious therapeutical challenge for the health care system in developed countries, and there has been a great emphasis on developing effective and safe therapies. Previous studies have revealed that several components of the metabolic syndrome are associated with an increased activation of the sympathetic nervous system. It has been shown that the sympathetic nerve activation is much higher in patients with metabolic syndrome, comparing with healthy subjects [4]. The inhibition of the adrenergic nervous system constitutes a suitable therapeutic approach for the treatment of the components of the metabolic syndrome [6]
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