Pharmacotoxicological screening on new derivatives of beta-phenylethylamine, potential agonists of beta3-adrenergic receptors

Beta3-adrenergic receptors (beta3-ARs) have been initially characterized in 1989. Afterwards, their tissue distribution was established: white and brown adipose tissue, central nervous system, myocardium (atrial and ventricular), blood vessels, smooth gastrointestinal muscles (stomach, small intestine, colon), gallbladder, urinary bladder, prostate, skeletal muscles. Non-clinical trials have demonstrated the major implication of beta3-ARs in glucose metabolism, implicitly, in insulin release, and also in obesity. Therefore, new compounds were synthesized starting from beta-phenylethylamine nucleus and substituted in various positions, for possible antidiabetic and÷or antiobesity action. In the present research, the antidiabetic action of newly synthesized compounds was investigated on an experimental model of alloxan-induced diabetes, administered in dose of 130 mg÷kg body weight (bw), intraperitoneally (i.p.). After 14 days of treatment, glycemia and enzymes involved in homeostasis of glucose metabolism, glucose-6-phosphate dehydrogenase (G6PD), glucose-6-phosphatase (G6Pase) and hexokinase were determined. Animals were then euthanized and histopathology examinations were performed on harvested liver, kidney, spleen and brain in order to document pathological changes induced by alloxan-induced diabetes and÷or by tested compounds. Glycemia in animals treated with the tested compounds decreased statistically significant for groups C2 and C3 (-42.13% and -37.2%, respectively), compared to diabetic control group. C2 was also the compound to favorably modify the dynamics of determined enzymes, together with the display of very good safety profile supported by minor, non-significant, histopathological changes.