Novel anti-inflammatory undecapeptides that contain anisolyated glutamic acid derivatives.

Abstract

In various animal models of tissue injury, corticotropin-releasing factor (CRF) and related peptides inhibit swelling, edema and loss of protein from the vascular compartment. To search for smaller peptide segments of CRF that might retain anti-inflammatory activity, the authors tested peptides similar to the carboxy terminals of ovine (o) and human/rat (h/r) CRF. Also, because h/rCRF(35-39), -Arg-Lys-Leu-Met-Glu-, resembles Arg-Lys-Leu-Leu-Glu-, a sequence found in many intermediate filament proteins, analogous peptides were evaluated. Ovine CRF(21-41), -Met-Thr-Lys-Ala-Asp-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys- Leu-Asp-Ile-Ala-NH2, its carboxy terminal carboxyl derivative, oCRF(21-41)-OH, and the fragments, oCRF(26-41) and oCRF(30-41), were inactive when assayed at 5 mg/kg i.v. on edema induced in the pentobarbital-anesthetized rat's hindpaw after immersion in 58 degrees C water for 1 min. Crude peptides, D-Leu-Ala-Thr-D-Tyr-Arg-Lys-Leu-Leu-Glu-Ile-D-Leu-NH2 and D-Ala-His-Ser-D-Asn-Arg-Lys-Leu-Leu-Glu-Ile-D-Leu-NH2, were found to have activity in this bioassay. Characterization of the structures within the crude mixture revealed that substitution of the glutamic acid residue with an anisolyated glutamic acid (2-amino-5-(methoxyphenyl)-5-oxopentanoic acid) derivative, designated as (A*), increased the overall potency. The glutamyl-anisole derivative was a by-product of the temperature-dependent Friedel-Crafts acylation reaction that occurs during hydrogen fluoride cleavage of glutamyl-containing peptides.(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: H A Thomas, N Ling, E T Wei, F Berree, A Cobas, H Rapoport
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 267 Issue 3 Pg. 1321-6 (Dec 1993) ISSN: 0022-3565 [Print] United States
• PMID: 7903386 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Glutamates
• Oligopeptides
• Receptors, Corticotropin-Releasing Hormone
• Receptors, Neurotensin
• Glutamic Acid

Topics

• Amino Acid Sequence
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (metabolism, pharmacology)
• Glutamates (metabolism, pharmacology)
• Glutamic Acid
• Male
• Molecular Sequence Data
• Oligopeptides (metabolism, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Corticotropin-Releasing Hormone (metabolism)
• Receptors, Neurotensin (metabolism)