NPY, PYY, PYY3_36, and PP are a class of polypeptide hormones that belong to the neuropeptide Y family. These peptides act through five receptor subtypes -NPY Y1-Y5 (Y6 subtype is found in mouse but not in primates or rats). Y1R is localized primarily in the brain and in the vasculature, while Y5R is found almost exclusively in the hypothalamus. Y2R is present in both the gastrointestinal tract and in the hypothalamus and is an autoreceptor, which negatively regulates NPY secretion. Y4R is located in both the brainstem and the NTS. NPY and PYY bind preferentially to Y1R, Y2R, and Y5R. PYY is cleaved by dipeptidylpeptidase-IV (DPP-IV) to give PYY3 36 which is selective for Y2R over the other receptors. PP is the only member of this peptide family that binds preferentially to Y4R. Roles for Y1R and Y5R in natural feeding have not been fully established. In contrast, Y2R and Y4R are believed to participate in the regulation of body weight since PYY3 36 and PP have been shown to reduce food intake in rodent and non-human primate models [65,66]. Modified versions of PYY3 36 are currently under clinical evaluation . The mechanisms-of-action by which PYY3 36 and PP exert their anorectic activities are not known, but may involve vagal afferent pathways that proceed through the brain stem to the hypothalamus . A review of the major developments in this area was last published in 2003 .
3.4.1. NPY Y2R and Y4R agonists
New Y2R and Y4R agonists are peptidic derivatives derived from NPY or PYY. N-terminal acylation of PYY fragments such as PYY26 36 and PYY27 36 has provided Y2R agonists such as 33 with good binding affinities and receptor subtype selectivities . PEGylated analogs of these fragments have been prepared to extend to half-life. A series of 2,7-D/L-diaminosuberic acid derivatives containing two pentapeptide fragments derived from the C-terminal of NPY (i.e., NPY32 36) have exhibited good Y4R binding and functional activity and selectivity against the other NPY receptor subtypes . Compound 34 (K = 0.95 nM; EC50 = 14.8 nM) inhibited 2 and 4h food intake in fasted mice following intraperitoneal administration (100 nmol/mouse), but had no effects on food intake in Y4R KO mice. Both compound 34 and PP exhibited similar binding affinities, but PP was > 100-fold more active in a cAMP functional assay. The difference between the binding and functional activities of these compounds was attributed to the presence of low [Na + ] concentrations in the membrane preparations used for binding.
3.4.2. NPY Y5R antagonists
The published data on Y5R antagonists have provided a conflicting picture of the role of this receptor in body weight regulation. Several antagonists have been shown to decrease food intake in various rodent models, but were later found to be an-orectic in Y5R KO mice . Other antagonists with good central exposure were inactive in DIO rodent models despite high binding affinities and good functional potencies . In the last year, however, several reports have appeared that suggest Y5R may be physiologically important in obesity. Most noteworthy, extensive effort has been devoted to proving specificity-of-action.
A tetrahydrocarbazole urea derivative 35 (FMS586, IC50 = 4.3 nM) was shown to inhibit fasting-induced re-feeding behavior and transiently suppress natural feeding behavior in Wistar rats after oral doses of 25-100 mg/kg . Compound 35 did not induce c-Fos expression after oral administration as measured by immunohistochemical analysis, but blocked hPP-induced c-Fos expression in Y5R-positive cells, thus demonstrating in vivo Y5 antagonism.
A phenylcyclohexylamine derivative 36 (rat and human K = 1.8 nM) was also found to decrease food intake and body weight in a 28-day study in DIO rats . This cyclohexyl compound was derived from a biphenyl analog 37 (K = 1.1 nM) which had a mutagenicity liability. Interestingly, compounds 36 and 37 were equipotent in the binding assay despite different three-dimensional conformations.
A tricyclic derivative 38 (L-152804) has been studied in different rodent models of obesity [76,77]. This compound showed moderate Y5R binding affinity (mY5R = 44 nM, rY5 K = 31 nM, Ca2+ IC50 = 210 nM) and was claimed to have little off-target activity (no significant cross reactivity with 120 other binding assays and seven enzyme assays). Compound 38 decreased body-weight gain in DIO mice, reduced adipose tissue mass, and improved DIO-associated hyperinsulinemia. It was specifically reported that high and sustained ROs were required for activity. Compound 38 was inactive in Y5R KO mice. A patent application has claimed that 38 can prevent the decrease in metabolic rate and energy expenditure that can occur with food restriction and loss of body weight .
The carbamoyl derivative 39 has been previously disclosed in the patent application literature as a Y5R antagonist . A new paper describes methods for quantifying 39 in human plasma and urine to support human pharmacokinetic studies . This class of compounds is reported to decrease appetite while increasing metabolic rate [79,80].
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