Antiobesity Effect of a Short-Length Peptide YY Analogue after Continuous Administration in Mice

• Published in: ACS medicinal chemistry letters Vol. 8; no. 6; pp. 628 - 631
• Main Authors: Nishizawa, Naoki, Niida, Ayumu, Masuda, Yasushi, Kumano, Satoshi, Yokoyama, Kotaro, Hirabayashi, Hideki, Amano, Nobuyuki, Ohtaki, Tetsuya, Asami, Taiji
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.06.2017; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Letter; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; Antiobesity; Y2 receptor (Y2R); Anorectic effect; Peptide YY (PYY); Short-length PYY analogue; BODY-WEIGHT; GHRELIN; REDUCES FOOD-INTAKE; OBESE; AGONISTS
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.7b00047

Gastrointestinal peptides such as peptide YY (PYY) can regulate appetite, which is relevant to the study of obesity. The intraperitoneal bolus administration of PYY3–36 and a 12-amino acid PYY analogue, benzoyl-[Cha27,28,36,Aib31]­PYY25–36 (1), showed similar anorectic activity by activating the Y2 receptor (Y2R). However, food intake inhibition and body weight loss were not observed upon continuous subcutaneous administration of 1 with osmotic pumps in diet-induced obese (DIO) mice. N-Terminal elongation of 1, together with amino acid substitution at position 24, led to a hydrophilic 14-amino acid peptide, Ac-[d-Hyp24,Cha27,28,36,Aib31]­PYY23–36 (18), that showed higher affinity and more potent agonist activity for Y2R and a robust anorectic activity with potency similar to that of PYY3–36. In addition, the continuous subcutaneous administration of 18 at 0.3 mg/(kg·day) induced significant body weight loss in DIO mice. These results suggest that a short-length PYY analogue can be a lead compound for antiobesity therapy in a sustained-release formulation.