N-Amino acid linoleoyl conjugates: anti-inflammatory activities.
Several N-linked amino acid-linoleic acid conjugates were studied for their potential as anti inflammatory agents. The parent molecule, N-linoleoylglycine was tested in an in vivo model, the mouse peritonitis assay where it showed activity in reducing leukocyte migration at doses as low as 0.3mg/kg when administered by mouth in safflower oil. Harvested peritoneal cells produced elevated levels of the inflammation-resolving eicosanoid 15-deoxy-Δ(13,14)-PGJ(2). These results are similar to those obtained in earlier studies with N-arachidonoylglycine. An in vitro model using mouse macrophage RAW cells was used to evaluate a small group of structural analogs for their ability to stimulate 15-deoxy-Δ(13,14)-PGJ(2) production. The d-alanine derivative was the most active while the d-phenylalanine showed almost no response. A high degree of stereo specificity was observed comparing the d and l alanine isomers; the latter being the less active. It was concluded that linoleic acid conjugates could provide suitable templates in a drug discovery program leading to novel agents for promoting the resolution of chronic inflammation.
Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, 364 Plantation St., Worcester, MA 01605, USA. sumner.burstein@umassmed.edu
Sumner
S
Burstein
Catherine
C
McQuain
Rebecca
R
Salmonsen
Benjamin
B
Seicol
D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D019787:Linoleic Acid / Q000737:chemistry*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000596:Amino Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019787:Linoleic Acid