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Neuropeptide Y (NPY) Y4 receptor selective agonists based on NPY(32-36): development of an anorectic Y4 receptor selective agonist with picomolar affinity. 2006

Ambikaipakan Balasubramaniam, and Deborra E Mullins, and Shu Lin, and Wexiu Zhai, and Zhiyong Tao, and Vikas C Dhawan, and Mario Guzzi, and James J Knittel, and Katy Slack, and Herbert Herzog, and Eric M Parker
Division of Gastrointestinal Hormones, Department of Surgery and Interdisciplinary Neurosciences Program, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA. Ambi.Bala@uc.edu

We have previously shown [Cys-Trp-Arg-Nva-Arg-Tyr-NH(2)](2), 1, to be a moderately selective neuropeptide Y (NPY) Y(4) receptor agonist. Toward improving the selectivity and potency for Y(4) receptors, we studied the effects of dimerizing H-Trp-Arg-Nva-Arg-Tyr-NH(2) using various diamino-dicarboxylic acids containing either di-, tri-, or tetramethylene spacers. These parallel dimers, 2A, 2B, 3, 4A, and 4B, and the corresponding linear tandem dimer and trimer analogues, 5 and 6, had enhanced selectivity and affinity for Y(4) receptors compared to 1 (Table 1). Substitution of Trp and Nva with Tyr and Leu, respectively, as in 2,7-d/l-diaminosuberic acid derivatized dimer, 7, resulted in a superior Y(4) selective agonist with picomolar affinity. Intraperitoneal (ip) injection of 7 potently inhibited food intake in fasted mice. Moreover, 7 (ip) inhibited the food intake in wild-type mice and not in Y(4)(-/-) knock-out mice, confirming that the actions of 7 on food intake are not due to global effects, but specifically mediated Y(4) receptors.

UI MeSH Term Description Entries
D007274 Injections, Intraperitoneal Forceful administration into the peritoneal cavity of liquid medication, nutrient, or other fluid through a hollow needle piercing the abdominal wall. Intraperitoneal Injections,Injection, Intraperitoneal,Intraperitoneal Injection
D008297 Male Males
D008810 Mice, Inbred C57BL One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases. Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D009479 Neuropeptides Peptides released by NEURONS as intercellular messengers. Many neuropeptides are also hormones released by non-neuronal cells. Neuropeptide
D009842 Oligopeptides Peptides composed of between two and twelve amino acids. Oligopeptide
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D004435 Eating The consumption of edible substances. Dietary Intake,Feed Intake,Food Intake,Macronutrient Intake,Micronutrient Intake,Nutrient Intake,Nutritional Intake,Ingestion,Dietary Intakes,Feed Intakes,Intake, Dietary,Intake, Feed,Intake, Food,Intake, Macronutrient,Intake, Micronutrient,Intake, Nutrient,Intake, Nutritional,Macronutrient Intakes,Micronutrient Intakes,Nutrient Intakes,Nutritional Intakes
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001067 Appetite Depressants Agents that are used to suppress appetite. Anorectic,Anorectic Agent,Anorectics,Anorexic Drug,Anorexigenic Drug,Appetite Depressant,Appetite Suppressant,Appetite Suppressants,Appetite-Depressing Drug,Appetite-Suppressant Drug,Anorectic Agents,Anorexic Drugs,Anorexigenic Drugs,Appetite-Depressing Drugs,Appetite-Suppressant Drugs,Agent, Anorectic,Agents, Anorectic,Appetite Depressing Drug,Appetite Depressing Drugs,Appetite Suppressant Drug,Appetite Suppressant Drugs,Depressant, Appetite,Depressants, Appetite,Drug, Anorexic,Drug, Anorexigenic,Drug, Appetite-Depressing,Drug, Appetite-Suppressant,Drugs, Anorexic,Drugs, Anorexigenic,Drugs, Appetite-Depressing,Drugs, Appetite-Suppressant,Suppressant, Appetite,Suppressants, Appetite
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships

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