New Potential Beta-3 Adrenergic Agonists with Beta- Phenylethylamine Structure, Synthesized for the Treatment of Dyslipidemia and Obesity

Abstract

Beta-3 adrenergic receptors have important physiological implications, being expressed in many places in the body, including brown adipose tissue. Of the effects studied in preclinical research on lipid metabolism attributable to stimulation of these receptors, we can mention the increased thermogenesis and metabolic rate in the brown adipose tissue, reduction of body weight in obese diabetic rats, lowering of intra-abdominal and subepithelial fat in nonobese and nondiabetic rats, decrease of triglyceride, and increase of HDL cholesterol levels. Carbohydrate metabolism is also changed by beta-3 adrenergic agonists, the most prevalent effects being blood glucose lowering in diabetic rats, increasing insulin secretion of the pancreas, or increasing glucose tolerance. Metabolic effects of 13 newly synthesized compounds of beta-phenylethylamine structure and reference BRL 37344 were investigated in order to identify a potential affinity for beta-3 adrenergic receptors. The antidiabetic and hypolipemiant effects were investigated on a rat model of alloxan-induced diabetes. The results demonstrated that new betaphenylethylamine derivatives produced marked biological activity over lipid profile. All compounds have markedly decreased the values of total cholesterol, LDL cholesterol, and triglycerides and also have increased the values of antiatherogenic HDL cholesterol. The effects were significantly more intense than the reference substance BRL 37344.

Everything You Always Wanted to Know about β3-AR * (* But Were Afraid to Ask)

“…All of these compounds markedly decreased levels of total cholesterol, LDL cholesterol, and triglycerides and increased the values of antiatherogenic HDL cholesterol. Moreover, the effects were significantly more intense than the reference substance BRL37344 [128]. In light of these considerations it appears that, although theoretically appealing, the amount of data that is currently available is not enough for β 3 -AR agonists to proceed into a clinical stage and more insights into the receptor physiology are ultimately needed for this purpose.…”

Epigenetic Regulators of White Adipocyte Browning

“…Cold or β-AR agonists can activate BAT and induce mature white adipocyte conversion to beige adipocytes [12]. However, prolonged exposure to cold is not therapeutically relevant and the usage of β-AR agonists for therapeutic purposes in treating dyslipidemia and obesity is still in question with their associated side effects [13,14]. Hence, in identifying potential therapeutic targets, it is essential to focus on different epigenetic regulators associated with white adipocyte differentiation and their browning.…”