Dead end for NPY Y₅-receptor antagonists?

Neuropeptide Y (NPY) is thought to have a key role in stimulating feeding, and its receptors are thus viewed as attractive appetite-suppressant drug targets for treating obesity. Of the known NPY receptors, previous investigations have implicated the Y₅ and Y₁ receptors as the most probable candidates for mediating the effects of NPY on food intake, and these receptors have both been the focus of considerable drug discovery efforts. But by assessing the effects of a highly selective and potent Y₅-receptor antagonist in rats, Turnbull et al. have now provided strong evidence that the Y₅ receptor is not a significant regulator of feeding behaviour.

The small-molecule Y₅-receptor antagonist NPY5RA-972 is at least 1,000-fold selective for the Y₅ receptor in a commercially available panel of 129 binding assays (which included assays for NPY receptors and a wide range of other neuropeptide receptors), and has good penetration into the central nervous system. Although NPY5RA-972 inhibited the marked and dose-dependent increase in food intake induced by a selective Y₅-receptor agonist, it had no significant effect on the increase in food intake induced by NPY or by 24 hours fasting in normal or genetically obese rats. And chronic administration of NPY5RA-972 had no effect on food intake or body weight in normal rats or rats that were obese owing to their diet.

So, why are these data in such contrast to previous evidence supporting the Y₅ receptor as a promising anti-obesity target? In part, it seems that some compounds used in previous studies might have activities in addition to Y₅-receptor antagonism that could be responsible for their effects on feeding behaviour. This conclusion is supported by the observation that such compounds inhibit feeding behaviour in mice that lack the Y₅ receptor, emphasizing the value of receptor knockout mice in defining the mode of action of drugs. Indeed, there is good evidence from studies in Y₁-receptor-deficient mice that the Y₁ receptor has a key role in NPY-induced feeding, and it seems likely that this is where efforts to target the activity of NPY will now be most concentrated. And in general, the study by Turnbull and colleagues serves as a warning that the effects of selective receptor activation might not necessarily be a good predictor of the importance of that receptor in more natural circumstances.