Abstract
In an attempt to produce more powerful (effective) bombesin/GRP receptor antagonists, the D forms of Trp or Trp analog (Tpi) were introduced at position 6 in two pseudononapeptides, Leu13ψ(CH2NH)Leu14-bombesin(6-14) and Leu13ψ(CH2NH)Phe14-bombesin (6-14). These antagonists were tested for their ability to inhibit basal and gastrin releasing peptide (GRP) (14-27)-induced amylase release from rat pancreatic acini in a superfusion assay. They were also assessed for the inhibition of 125I-Tyr4-bombesin binding to Swiss 3T3 and small cell lung carcinoma cell line H-345 and the mitogenic response of Swiss 3T3 cells induced by GRP(14-27). The peptides, when given alone, did not stimulate amylase secretion, but were able to inhibit gastrin releasing peptide (14-27)-induced amylase release. All of the antagonists showed strong binding affinities for Swiss 3T3 and H-345 cells and suppressed the GRP(14-27)-induced increase of [3H]thymidine incorporation into DNA of Swiss 3T3 cells at nanomolar concentrations. Antagonist D-Tpi6,Leu13ψ(CH2NH)Leu14-bombesin (6-14)(RC-3095) was slightly more potent in these assays than D-Trp6,Leu13ψ(CH2NH)Leu14-bombesin (6-14)(RC-3125). Nevertheless, D-Trp6,Leu13ψ(CH2NH)Phe14-bombesin (6-14) showed the highest binding affinity for Swiss 3T3 and H345 cells and it was the most potent inhibitor of GRP(14-27)-induced amylase secretion. This antagonist RC-3420 was particularly effective in inhibiting the growth of Swiss 3T3 cells, exhibiting an IC50 value less than 1 nM. Our work indicated that the substitution of D-Trp and D-Tpi at position 6 of the pseudononapeptide bombesin analogs (ψ13-14), in which the Met14 residue is replaced by Leu or Phe, results in potent bombesin/GRP antagonists with improved in vivo activity.
| Original language | English |
|---|---|
| Pages (from-to) | 593-600 |
| Number of pages | 8 |
| Journal | International Journal of Peptide and Protein Research |
| Volume | 38 |
| Issue number | 6 |
| State | Published - Dec 1 1991 |
| Externally published | Yes |
Fingerprint
ASJC Scopus subject areas
- Biochemistry
Cite this
Biological effects and receptor binding affinities of new pseudononapeptide bombesin/GRP receptor antagonists with N-terminal D-Trp or D-Tpi. / Radulovic, S.; Cai, R. Z.; Serfozo, P.; Groot, K.; Redding, T. W.; Pinski, J.; Schally, Andrew V.
In: International Journal of Peptide and Protein Research, Vol. 38, No. 6, 01.12.1991, p. 593-600.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Biological effects and receptor binding affinities of new pseudononapeptide bombesin/GRP receptor antagonists with N-terminal D-Trp or D-Tpi
AU - Radulovic, S.
AU - Cai, R. Z.
AU - Serfozo, P.
AU - Groot, K.
AU - Redding, T. W.
AU - Pinski, J.
AU - Schally, Andrew V
PY - 1991/12/1
Y1 - 1991/12/1
N2 - In an attempt to produce more powerful (effective) bombesin/GRP receptor antagonists, the D forms of Trp or Trp analog (Tpi) were introduced at position 6 in two pseudononapeptides, Leu13ψ(CH2NH)Leu14-bombesin(6-14) and Leu13ψ(CH2NH)Phe14-bombesin (6-14). These antagonists were tested for their ability to inhibit basal and gastrin releasing peptide (GRP) (14-27)-induced amylase release from rat pancreatic acini in a superfusion assay. They were also assessed for the inhibition of 125I-Tyr4-bombesin binding to Swiss 3T3 and small cell lung carcinoma cell line H-345 and the mitogenic response of Swiss 3T3 cells induced by GRP(14-27). The peptides, when given alone, did not stimulate amylase secretion, but were able to inhibit gastrin releasing peptide (14-27)-induced amylase release. All of the antagonists showed strong binding affinities for Swiss 3T3 and H-345 cells and suppressed the GRP(14-27)-induced increase of [3H]thymidine incorporation into DNA of Swiss 3T3 cells at nanomolar concentrations. Antagonist D-Tpi6,Leu13ψ(CH2NH)Leu14-bombesin (6-14)(RC-3095) was slightly more potent in these assays than D-Trp6,Leu13ψ(CH2NH)Leu14-bombesin (6-14)(RC-3125). Nevertheless, D-Trp6,Leu13ψ(CH2NH)Phe14-bombesin (6-14) showed the highest binding affinity for Swiss 3T3 and H345 cells and it was the most potent inhibitor of GRP(14-27)-induced amylase secretion. This antagonist RC-3420 was particularly effective in inhibiting the growth of Swiss 3T3 cells, exhibiting an IC50 value less than 1 nM. Our work indicated that the substitution of D-Trp and D-Tpi at position 6 of the pseudononapeptide bombesin analogs (ψ13-14), in which the Met14 residue is replaced by Leu or Phe, results in potent bombesin/GRP antagonists with improved in vivo activity.
AB - In an attempt to produce more powerful (effective) bombesin/GRP receptor antagonists, the D forms of Trp or Trp analog (Tpi) were introduced at position 6 in two pseudononapeptides, Leu13ψ(CH2NH)Leu14-bombesin(6-14) and Leu13ψ(CH2NH)Phe14-bombesin (6-14). These antagonists were tested for their ability to inhibit basal and gastrin releasing peptide (GRP) (14-27)-induced amylase release from rat pancreatic acini in a superfusion assay. They were also assessed for the inhibition of 125I-Tyr4-bombesin binding to Swiss 3T3 and small cell lung carcinoma cell line H-345 and the mitogenic response of Swiss 3T3 cells induced by GRP(14-27). The peptides, when given alone, did not stimulate amylase secretion, but were able to inhibit gastrin releasing peptide (14-27)-induced amylase release. All of the antagonists showed strong binding affinities for Swiss 3T3 and H-345 cells and suppressed the GRP(14-27)-induced increase of [3H]thymidine incorporation into DNA of Swiss 3T3 cells at nanomolar concentrations. Antagonist D-Tpi6,Leu13ψ(CH2NH)Leu14-bombesin (6-14)(RC-3095) was slightly more potent in these assays than D-Trp6,Leu13ψ(CH2NH)Leu14-bombesin (6-14)(RC-3125). Nevertheless, D-Trp6,Leu13ψ(CH2NH)Phe14-bombesin (6-14) showed the highest binding affinity for Swiss 3T3 and H345 cells and it was the most potent inhibitor of GRP(14-27)-induced amylase secretion. This antagonist RC-3420 was particularly effective in inhibiting the growth of Swiss 3T3 cells, exhibiting an IC50 value less than 1 nM. Our work indicated that the substitution of D-Trp and D-Tpi at position 6 of the pseudononapeptide bombesin analogs (ψ13-14), in which the Met14 residue is replaced by Leu or Phe, results in potent bombesin/GRP antagonists with improved in vivo activity.
UR - http://www.scopus.com/inward/record.url?scp=0026338583&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0026338583&partnerID=8YFLogxK
M3 - Article
C2 - 1726427
AN - SCOPUS:0026338583
VL - 38
SP - 593
EP - 600
JO - International Journal of Peptide and Protein Research
JF - International Journal of Peptide and Protein Research
SN - 0367-8377
IS - 6
ER -