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

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 morphinomimetic activity both in vivo and in vitro. The partially modified retro-inverso analogues: [pGlu6 psi(NH-CO)(RS)-Phe7]SP-(6-11) (analogue II) and [pGlu6,Phe8 psi(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 (t1/2) 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 II 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 microM) 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.(ABSTRACT TRUNCATED AT 250 WORDS)