Metabolically stable analogues of substance P: Persistent action of partially modified retro-inverso analogues of substance P on rat parotid and hypothalamic slices

Michael Chorev, Eli Rubini, Yo'av Hart, Chaim Gilon, Uri Wormser, Zvi Selinger*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

In a search for metabolically stable analogues of substance P (SP) the hexapeptide [pGlu6]SP-(6-11) was modified by reversal of the direction of a single amide bond. This novel peptide modification reverses the direction of the amide bonds at the peptide backbone but attempt to retain the topology of the amino acid side-chains at the peptide surface. The partial retro-inverso modification was successfully applied in a previous study for enkephalin analogues which were found to have potent and protracted mophinomimetic activity both in vivo and in vitro. The partially modified retro-inverso analogues: [pGlu6ψ(NH-CO)(RS)-Phe7]SP-(6-11) (analogue II) and [pGlu6, Phe8ψ(NH-CO)Gly9]SP-(6-11) (analogue III) were tested on guinea-pig ileum and for K+ release from rat parotid slices. Metabolic stability of the analogues was measured by their ability to produce persistent K+ release from parotid slices, their half life time (t 1 2) in the rat parotid and hypothalamic slice systems and their resistance to proteolytic cleavage by chymotrypsin, pepsin, papain and pronase. Analogue II was devoid of biological activity and was slowly degraded in the parotid system and by several proteases. Analogue III was a full agonist of the SP-P receptor with a potency of 22 and 15% of the parent compound I, in the guinea-pig ileum and parotid slice system respectively. Pretreatment of the guinea-pig ileum with atropine (0.3 μM) had no effect on the potency of analogue III. On the other hand, when tested on rat vas deferens (an SP-E system), analogue III was about 20-fold more potent than the parent compound I. Analogue III was not degraded by rat parotid or hypothalamic slices and was resistant to proteolytic cleavage by chymotrypsin, pepsin, thermolysin and pronase, and only degraded at a slow rate by papain (t 1 2 ∼ 2.5 h).

Original languageEnglish
Pages (from-to)187-195
Number of pages9
JournalEuropean Journal of Pharmacology
Volume127
Issue number3
DOIs
StatePublished - 15 Aug 1986

Keywords

  • Guinea-pig ileum
  • Metabolically stable analogues
  • Partially modified retro-inverso
  • Rat hypothalamic slices Rat parotid slices
  • Substance P

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