TY - JOUR
T1 - Metabolically stable analogues of substance P
T2 - Persistent action of partially modified retro-inverso analogues of substance P on rat parotid and hypothalamic slices
AU - Chorev, Michael
AU - Rubini, Eli
AU - Hart, Yo'av
AU - Gilon, Chaim
AU - Wormser, Uri
AU - Selinger, Zvi
PY - 1986/8/15
Y1 - 1986/8/15
N2 - 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).
AB - 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).
KW - Guinea-pig ileum
KW - Metabolically stable analogues
KW - Partially modified retro-inverso
KW - Rat hypothalamic slices Rat parotid slices
KW - Substance P
UR - http://www.scopus.com/inward/record.url?scp=0022458619&partnerID=8YFLogxK
U2 - 10.1016/0014-2999(86)90363-8
DO - 10.1016/0014-2999(86)90363-8
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C2 - 2428641
AN - SCOPUS:0022458619
SN - 0014-2999
VL - 127
SP - 187
EP - 195
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 3
ER -