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Peripheral administration of PYY 3-36 , a fragment of peptide YY (PYY), has been reported to reduce food intake by activating the neuropeptide Y2 receptor (Y2R). An N-terminally truncated PYY analogue, benzoyl-[Ala 26 ,Ile 28,31 ]PYY(25-36) ( 1 ), showed a relatively potent agonist activity for Y2R but a weak anorectic activity by intraperitoneal administration (2000 nmol/kg) in lean mice because of its markedly poor biological stability in the mouse serum. Notably, two cyclohexylalanine (Cha) substitutions for Tyr residues at positions 27 and 36 ( 4 ) improved the stability in the mouse serum concomitant with enhanced anorectic activity. Further optimization at positions 27, 28, 30, and 31 revealed that 21 , containing Cha 28 and Aib 31 residues, showed a more potent anorectic activity than PYY 3-36 at a low dose of 300 nmol/kg. The minimum effective dose by intraperitoneal administration of 21 was 30 nmol/kg (ca. 52 μg/kg) in mice, suggesting the biologic potential of short-length PYY 3-36 analogues with a potent anorectic effect.

A Short-Length Peptide YY Analogue with Anorectic Effect in Mice