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Synthesis of an intrinsically radiolabeled enkephalin analog: [p‐tritio‐phenylalanyl] 4 ‐norleucyl 5 ‐enkephalin

1978; Wiley; Volume: 14; Issue: 3 Linguagem: Inglês

10.1002/jlcr.2580140311

1099-1344

Alan R. Day, Richard J. Freer,

Chemical Synthesis and Analysis

Abstract In a previous study methionine‐enkephalin (H‐Tyr‐Gly‐Gly‐Phe‐Met‐OH) and four analogs and homologs were synthesized and compared to morphine with respect to their ability to inhibit electrically evoked contractions of the isolated guinea pig ileum. The compounds were: Tyr‐Gly‐Gly‐Phe‐Leu (Leu 5 ‐enkephalin), Tyr‐Gly‐Gly‐Phe (des‐Met 5 ‐enkephalin), Tyr‐Gly‐Gly‐Phe‐Nle (Nle 5 ‐enkephalin) and Tyr‐Gly‐Gly‐[p‐chloro‐Phe]‐Nle ([p‐chloro‐Phe] 4 ‐Nle 5 ‐enkephalin). The IC 50 concentrations on the guinea pig ileum assay were 3.0 × 10 −7 M, 4.0 × 10 −5 M, 1.1 × 10 −7 M and 1.6 × 10 −7 M respectively. The IC 50 for Met 5 ‐enkephalin was 5.0 × 10 −8 M and for morphine 2.0 × 10 −7 M. These data indicate that the methionine residue is important for biological activity and that norleucine is a more acceptable substitution at this position than is leucine. Therefore, the [p‐chloro‐Phe] 4 ‐[Nle] 5 ‐enkephalin was synthesized, dehalogenated by catalytic hydrogenation in the presence of 3 H 2 to yield the intrinsically labeled [p‐tritio‐Phe] 4 ‐Nle 5 ‐enkephalin. The labeled peptide (9 Ci/mmole) was completely stable for at least 9 months at −20°C in 50% aqueous acetic acid.