Orexigenic effect of the melanocortin MC4 receptor antagonist HS014 is inhibited only partially by neuropeptide YY1 receptor selective antagonists

Neuropeptide Y (NPY) and melanocortin (MC) peptides have opposite effects o n food intake: NPY-like peptides and MC receptor antagonists stimulate feed ing and increase body weight, whereas melanocortins and NPY antagonists inh ibit food intake. In this study we tested whether the orexigenic effect of the selective MC4 receptor antagonist HS014 (1 nmol) could be inhibited by three different NPY antagonists, (R)-N-2-(diphenylacetyl)-N-[(4-hydroxy-phe nyl)methyl]- D-argininamide (BIBP3226), (R)-N-[[4-(aminocarbonylaminomethyl )-phenyl]methyl]-N-2-(diphenylacetyl)-argininamide-trifluoroacetate (BIBO33 04), and decapeptide [D-Tyr(27,36)D-Thr(32)]NPY27-36, after icv administrat ion in freely feeding male rats. All three NPY receptor antagonists inhibit ed the orexigenic effects of HS014 partially and with markedly different po tency. [D-Tyr(27,36)D-Thr(32)]NPY27-36 was active only in subconvulsive dos e. The NPY Y-1 selective antagonist BIBP3226 was more effective in inhibiti ng the effect of HS014 than BIBO3304 despite in vitro data indicating that BIBP3226 is about 10 times less potent than BIBO3304 at NPY Y-1 receptor. A n enantiomer of BIBO3304, BIBO3457, failed to inhibit HS014-induced feeding , indicating that the effects of BIBO3304 were stereoselective. These resul ts suggest that stimulation of food intake caused by weakening of melanocor tinergic tone at the MC4 receptor is partially but not exclusively related to NPY Y-1 receptor activation.