A potent and selective NPYY5 antagonist reduces food intake but not through blockade of the NPYY5 receptor

AIM: These studies were performed to test the hypothesis that endogenous neuropeptide Y ( NPY) acting on the NPY Y-5 receptor subtype contributes to the control of food intake. The hypothesis was tested using S 25585-a newly synthesized NPY Y-5 receptor antagonist. METHODS AND RESULTS: S 25585 was shown to be a high- affinity antagonist of the NPY Y-5 receptor subtype ( IC50 5 nM) with no significant affinity toward other NPY receptor subtypes and over 40 other receptors, channels or uptake systems. S 25585 ( 7.5 mg/ kg, i. p.) did not induce a conditioned taste aversion, significantly alter need- induced sodium appetite or induce pica, suggesting that at this dose the compound did not induce illness or malaise. In satiated rats, S 25585 ( 5.0 and 7.5 mg/ kg, i. p.) significantly decreased the overfeeding induced by i. c. v. injection of NPY ( 1 mug) and the highly selective NPY Y-5 receptor agonist [hPP (1-17), Ala(31), Aib(32)] NPY ( 0.7 mug). In rats fasted for 4 h immediately before the dark phase, analysis of the microstructure of feeding behavior revealed that S 25585 significantly increased latency to eat and significantly decreased the duration and size of the meals without altering the meal number or eating rate. Analysis of the behavioral satiety sequence at this time revealed that the animals passed through the normal pattern of feeding, grooming and resting. Although S 25585 appeared to be influencing a physiological system controlling appetite, this does not involve the NPY Y-5 receptor since the antagonist also markedly reduced food intake in the NPY Y-5 knockout mouse. CONCLUSIONS: The results presented do not support a role for the NPY Y-5 receptor in the control of food intake. The results further illustrate that it is imperative that the activity of any new NPY Y-5 antagonist be assessed in the NPY Y-5 knockout mouse before assuming that its effect on food intake is due to blockade of this receptor.