Highly potent substance P antagonists substituted with beta-phenyl- or beta-benzyl-proline at position 10

European Journal of Pharmacology
S LavielleG Chassaing

Abstract

In the guinea-pig ileum tissue, [Pro9]substance P, a tachykinin NK1 receptor selective agonist and septide, [pGlu6,Pro9]-substance P-(6-11), do not interact with the same receptor as shown by the different inhibitory profiles of GR 72251 and [D-Pro9,Pro10,Trp11]substance P. Substitution at position 10 of the D-Pro9-Pro10 moiety with bulky N-methylated amino acids increased the antagonist potency for the tachykinin NK1 receptor without affecting that for the 'septide-sensitive receptor'. The incorporation of a trans-beta-L-substituted proline in position 10, for example a benzyl group (beta-benzyl-L-proline), afforded a potent antagonist active in the nanomolar range. For GR 82334, this increase in potency was obtained at the expense of selectivity for tachykinin NK1 and 'septide-sensitive' receptors.

References

Jul 1, 1990·Journal of Medicinal Chemistry·P WardJ R Brown
Jan 12, 1987·Life Sciences·D RegoliP D'Orléans-Juste
Mar 1, 1959·British Journal of Pharmacology and Chemotherapy·O ARUNLAKSHANA, H O SCHILD
Jan 1, 1948·Journal of the American Chemical Society·P L JULIAN, W J KARPEL

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Citations

Sep 1, 1995·General Pharmacology·C A Maggi
Aug 12, 1999·European Journal of Pharmacology·A Saria
Feb 27, 2003·European Journal of Biochemistry·Sandrine SaganOlivier Lequin
Oct 16, 2004·The Journal of Peptide Research : Official Journal of the American Peptide Society·S ClaudelS Lavielle
Apr 23, 2002·The Journal of Peptide Research : Official Journal of the American Peptide Society·E SachonS Sagan
Jul 1, 1997·The Journal of Peptide Research : Official Journal of the American Peptide Society·P W BauresR L Johnson

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