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

Peripheral administration
of PYY3–36, 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-[Ala26,Ile28,31]­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 Cha28 and
Aib31 residues, showed a more potent anorectic activity
than PYY3–36 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 PYY3–36 analogues with
a potent anorectic effect.