Ha. Thomas et al., NOVEL ANTIINFLAMMATORY UNDECAPEPTIDES THAT CONTAIN ANISOLYLATED GLUTAMIC-ACID DERIVATIVES, The Journal of pharmacology and experimental therapeutics, 267(3), 1993, pp. 1321-1326
In various animal models of tissue injury, corticotropin-releasing fac
tor (CRF) and related peptides inhibit swelling, edema and loss of pro
tein from the vascular compartment. To search for smaller peptide segm
ents of CRF that might retain anti-inflammatory activity, the authors
tested peptides similar to the carboxy terminals of ovine (o) and huma
n/rat (h/r) CRF. Also, because h/rCRF(35-39), -Arg-Lys-Leu-Met-Glu-, r
esembles -Arg-Lys-Leu-Leu-Glu-, a sequence found in many intermediate
filament proteins, analogous peptides were evaluated. Ovine CRF(21-41)
, n-Ala-His-Ser-Asn-Arg-Lys-Leu-Leu-Asp-Ile-Ala-NH2, its carboxy termi
nal carboxyl derivative, oCRF(21-41 )-OH, and the fragments, oCRF(26-4
1) and oCRF(30-41), were inactive when assayed at 5 mg/kg i.v. on edem
a induced in the pentobarbital-anesthetized rat's hindpaw after immers
ion in 58-degrees-C water for 1 min. Crude peptides, eu-Ala-Thr-D-Tyr-
Arg-Lys-Leu-Leu-Glu-Ile-D-Leu-NH2 and a-His-Ser-D-Asn-Arg-Lys-Leu-Leu-
Glu-Ile-D-Leu-NH2, were found to have activity in this bioassay. Chara
cterization of the structures within the crude mixture revealed that s
ubstitution of the glutamic acid residue with an anisolylated glutamic
acid (2-amino-5-(methoxyphenyl)-5-oxopentanoic acid) derivative, desi
gnated as (A), increased the overall potency. The glutamyl-anisole de
rivative was a by-product of the temperature-dependent Friedel-Crafts
acylation reaction that occurs during hydrogen fluoride cleavage of gl
utamyl-containing peptides. Several undecapeptides that contained D-am
ino acids and the anisolylated glutamic acid derivative were synthesiz
ed and characterized by high-performance liquid chromatography, amino
acid analysis, mass spectroscopy and nuclear magnetic resonance spectr
oscopy. The more potent peptides, u-Ala-Thr-D-Tyr-Arg-Lys-Leu-Leu-(A)
-Ile-D-Leu-NH2 and a-His-Ser-D-Asn-Arg-Lys-Leu-Leu-(A)-Ile-D-Leu-NH2
reduced epinephrine-induced pulmonary edema and heat-induced edema wit
h ED50 values of 0.04 and 0.05 mg/kg i.v., respectively.