Regulation of maternal food intake and mother-pup interactions by the Y5 receptor.
ABSTRACT Neuropeptide Y (NPY) is increased in the hypothalamus during lactation. To investigate the role of the NPY Y5 receptor during lactation, an antisense oligodeoxynucleotide (ODN) targeted to the NPY Y5 receptor, an equivalent scrambled ODN or vehicle, was chronically infused into the 3rd ventricle of lactating rats from day 8 postpartum. Y5 antisense ODN treatment reduced Y5 positive cell number in the paraventricular nucleus and resulted in significant reductions in food intake and litter growth. Litters from pair-fed vehicle treated dams gained significantly more weight than the litters of Y5 antisense ODN treated dams suggesting that decreased maternal food intake is not the only mechanism involved in suppressing litter weight gain. When mother-litter interaction was examined on day 13 pp, Y5 antisense ODN treated dams spent significantly less time on the nest and had significantly shorter nest bouts. These results suggest that in addition to regulating feeding behaviour, the Y5 receptor subtype may have previously unrecognised roles in the control of nesting behaviour during lactation with subsequent effects on litter growth rates.
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ABSTRACT: Optimization of HTS hit 1 for NPY Y5 receptor binding affinity, CYP450 inhibition, solubility and metabolic stability led to the identification of some orally available oxygen-linker derivatives for in vivo study. Among them, derivative 4i inhibited food intake induced by the NPY Y5 selective agonist, and chronic oral administration of 4i in DIO mice caused a dose-dependent reduction of body weight gain.Bioorganic & medicinal chemistry letters 11/2012; · 2.65 Impact Factor
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ABSTRACT: The proteolytic processing of neuropeptides has an important regulatory function and the peptide fragments resulting from the enzymatic degradation often exert essential physiological roles. The proteolytic processing generates, not only biologically inactive fragments, but also bioactive fragments that modulate or even counteract the response of their parent peptides. Frequently, these peptide fragments interact with receptors that are not recognized by the parent peptides. This review discusses tachykinins, opioid peptides, angiotensins, bradykinins, and neuropeptide Y that are present in the central nervous system and their processing to bioactive degradation products. These well-known neuropeptide systems have been selected since they provide illustrative examples that proteolytic degradation of parent peptides can lead to bioactive metabolites with different biological activities as compared to their parent peptides. For example, substance P, dynorphin A, angiotensin I and II, bradykinin, and neuropeptide Y are all degraded to bioactive fragments with pharmacological profiles that differ considerably from those of the parent peptides. The review discusses a selection of the large number of drug-like molecules that act as agonists or antagonists at receptors of neuropeptides. It focuses in particular on the efforts to identify selective drug-like agonists and antagonists mimicking the effects of the endogenous peptide fragments formed. As exemplified in this review, many common neuropeptides are degraded to a variety of smaller fragments but many of the fragments generated have not yet been examined in detail with regard to their potential biological activities. Since these bioactive fragments contain a small number of amino acid residues, they provide an ideal starting point for the development of drug-like substances with ability to mimic the effects of the degradation products. Thus, these substances could provide a rich source of new pharmaceuticals. However, as discussed herein relatively few examples have so far been disclosed of successful attempts to create bioavailable, drug-like agonists or antagonists, starting from the structure of endogenous peptide fragments and applying procedures relying on stepwise manipulations and simplifications of the peptide structures.Medicinal Research Reviews 06/2014; · 8.13 Impact Factor
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ABSTRACT: Optimization of lead compound 2 is described, mainly focusing on modification at the C-2 position of the benzimidazole core. Replacement of the phenyl linker of 2 with saturated rings resulted in identification of compound 8b which combines high Y5 receptor binding affinity with a good ADME profile leading to in vivo efficacy.Bioorganic & medicinal chemistry letters 09/2012; 22(21):6554-8. · 2.65 Impact Factor