New Antagonist Agents of Neuropeptide Y Receptors

The Neuropeptide Y (NPY) is a peptide of 36 amino acids, similar to the peptide YY (PYY) and to the pancreatic polypeptides (PP). At first, separated from the pig brain, the NPY is well-distributed in the mammals at the level of the central and peripheric nervous system. This neurotransmitter is present in strong concentrations in the nervous fiber of the brain, but equally as strong in the heart, the sympathetic glands, the blood vessels and the gastrointestinal tract. It is responsable for diverse phyisiological effects that exert themselves by way of specific receptors (Y). These Y receptors form a heterogeneous group and six subtypes have been identified up to now: Y1 to Y6. The NPY is involved in the control of appetite, strongly stimulating the intake of food, or performing a regulatory role on the HPA (hypothalamic-pituitary-adrenal) axis. It also presents anxiolytic and sedative properties that induce an increase in the blood pressure and affects the circadian rhythm. The search for agonists and antagonists of NPY could yield compounds which could be used in the treatment of pathologies related to food behavior or energy equilibrium disorders, such as diabetes, obesity, bulimia and anorexia. Also in the treatment of arterial hypertension, anxiety, depressions, epilepsia and sleeping disorders. The orexigenic effects of NPY could be mediated by it receptor NPY1 subtype5, which makes it possible to consider that is involved in the stimulating effect of the appetite of the neuropeptide Y. Recently, ligands of this receptor have been described. The first compound of nonpeptide structure with potent antagonist activity of the receptor NPY1, is BIBP 3226 (Fig.1), which was designed using the region C-terminal of the NPY6. Recent studies appear to confirm an important implication of the receptor NPY5 subtype in the control of food ingestion7. The first Y5-selective antagonists appeared in the patent literature in mid-19978. These compounds have something in common: an amino acid, phenylalanine (SR 120819A) and arginine (BIBP 3226) respectively, in the center part of the molecule. Also, the amino and carboxyl groups from the amino acid remain funtionalized in the form of amide. Likewise, the first selective NPY5 antagonists are appearing. One such example is JCF 104 (2-(naphtalen-1-yl)-3-phenylpropane-1,2diamine)9 (Fig. 1), which carries a rest of 2-amino-3phenylpropanamine, closely related to the aforementioned systems. Our objective is to search for new compounds that are non-peptidic selective antagonists of the Y5 receptor subtype. This line of research implies the presence of a phenylalanine and/or methyltyrosine rest in the central part of a molecule in which the carboxyl and amine groups of the amino acid are funtionalized as amide and carbamate respectively (Fig. 2).