A backbone-cyclic, receptor 5-selective somatostatin analogue: synthesis, bioactivity, and nuclear magnetic resonance conformational analysis.
Cyclo(PheN2-Tyr-D-Trp-Lys-Val-PheC3)-Thr-NH2 (PTR 3046), a backbone-cyclic somatostatin analogue, was synthesized by solid-phase methodology. The binding characteristics of PTR 3046 to the different somatostatin receptors, expressed in CHO cells, indicate high selectivity to the SSTR5 receptor. PTR 3046 is highly stable against enzymatic degradation as determined in vitro by incubation with rat renal homogenate and human serum. The biological activity of PTR 3046 in vivo was determined in rats. PTR 3046 inhibits bombesin- and caerulein-induced amylase and lipase release from the pancreas without inhibiting growth hormone or glucagon release. The major conformation of PTR 3046 in CD3OH, as determined by NMR, is defined by a type II' beta-turn at D-Trp-Lys and a cis amide bond at Val-PheC3.
Gilon
C
C
Department of Organic Chemistry, Hebrew University, Jerusalem, Israel.
Huenges
M
M
Mathä
B
B
Gellerman
G
G
Hornik
V
V
Afargan
M
M
Amitay
O
O
Ziv
O
O
Feller
E
E
Gamliel
A
A
Shohat
D
D
Wanger
M
M
Arad
O
O
Kessler
H
H
D000681:Amylases / Q000378:metabolism; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D001839:Bombesin / Q000494:pharmacology; D016466:CHO Cells; D002108:Ceruletide / Q000494:pharmacology; D006224:Cricetinae; D004797:Enzyme-Linked Immunosorbent Assay; D005934:Glucagon / Q000097:blood; D013006:Growth Hormone / Q000097:blood; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008049:Lipase / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D017481:Receptors, Somatostatin / Q000096:biosynthesis / Q000378:metabolism*
D001798:Blood Proteins; C111355:PTR 3046; D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin; D002108:Ceruletide; C094573:somatostatin receptor 5; D013006:Growth Hormone; D005934:Glucagon; D008049:Lipase; D000681:Amylases; D001839:Bombesin