Design, synthesis, and biological activities of potent and selective somatostatin analogues incorporating novel peptoid residues.
We report the synthesis, bioactivity, and structure-activity relationship studies of compounds related to the Merck cyclic hexapeptide c[Pro6-Phe7-d-Trp8-Lys9-Thr10-Phe11], L-363,301 (the numbering in the sequence refers to the position of the residues in native somatostatin). The Pro residue in this compound is replaced with arylalkyl peptoid residues. We present a novel approach utilizing beta-methyl chiral substitutions to constrain the peptoid side-chain conformation. Our studies led to molecules which show potent binding and increased selectivity to the hsst2 receptor (weaker binding to the hsst3 and hsst5 receptors compared to L-363, 301). In vivo, these peptoid analogues selectively inhibit the release of growth hormone but have no effect on the inhibition of insulin. The biological assays which include binding to five recombinant human somatostatin receptors carried out in two independent laboratories and in vivo inhibition of growth hormone and insulin provide insight into the relationship between structure and biological activity of somatostatin analogues. Our results have important implications for the study of other peptide hormones and neurotransmitters.
Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California 92093-0343, USA.
T A
TA
Tran
R H
RH
Mattern
M
M
Afargan
O
O
Amitay
O
O
Ziv
B A
BA
Morgan
J E
JE
Taylor
D
D
Hoyer
M
M
Goodman
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D015195:Drug Design; D013006:Growth Hormone / Q000097:blood; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D034444:Peptoids; D051381:Rats; D017208:Rats, Wistar; D017481:Receptors, Somatostatin / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D007328:Insulin; D010446:Peptide Fragments; D034444:Peptoids; D017481:Receptors, Somatostatin; C113342:cyclo(N-benzylglycyl-phenylalanyl-tryptophyl-lysyl-threonyl-phenylalanyl); C040704:cyclo(Pro-Phe-Trp-Lys-Thr-Phe); C113341:cyclo(beta-methyl-N-benzylglycyl-phenylalanyl-tryptophyl-lysyl-threonyl-phenylalanyl); D013004:Somatostatin; D013006:Growth Hormone