S-phenylpiracetam, a selective DAT inhibitor, reduces body weight gain without influencing locomotor activity

Abstract S -phenylpiracetam is an optical isomer of phenotropil, which is a clinically used nootropic drug that improves physical condition and cognition. Recently, it was shown that S -phenylpiracetam is a selective dopamine transporter (DAT) inhibitor that does not influence norepinephrine (NE) or serotonin (5-HT) receptors. The aim of the present study was to study the effects of S -phenylpiracetam treatment on body weight gain, blood glucose and leptin levels, and locomotor activity. Western diet (WD)-fed mice and obese Zucker rats were treated daily with peroral administration of S -phenylpiracetam for 8 and 12 weeks, respectively. Weight gain and plasma metabolites reflecting glucose metabolism were measured. Locomotor activity was detected in an open-field test. S -phenylpiracetam treatment significantly decreased body weight gain and fat mass increase in the obese Zucker rats and in the WD-fed mice. In addition, S -phenylpiracetam reduced the plasma glucose and leptin concentration and lowered hyperglycemia in a glucose tolerance test in both the mice and the rats. S -phenylpiracetam did not influence locomotor activity in the obese Zucker rats or in the WD-fed mice. The results demonstrate that S -phenylpiracetam reduces body weight gain and improves adaptation to hyperglycemia without stimulating locomotor activity. Our findings suggest that selective DAT inhibitors, such as S -phenylpiracetam, could be potentially useful for treating obesity in patients with metabolic syndrome with fewer adverse health consequences compared to other anorectic agents.