Somatostatin receptor 1 selective analogues: 3. Dicyclic peptides.
The binding affinity of short chain somatostatin (SRIF) analogues at the five human SRIF receptors (sst) was determined to identify sterically constrained somatostatin receptor subtype 1 (sst(1)) selective scaffolds. Des-AA(1,2,4,13)-[d-Trp(8)]SRIF (2) retained high binding affinity at all receptors but sst(1), Des-AA(1,2,4,5)-[d-Trp(8)]SRIF (3) at sst(4) and sst(5), and Des-AA(1,2,4,5,13)-[d-Trp(8)]SRIF (4) at sst(2) and sst(4) (AA = amino acid). Des-AA(1,2,4,12,13)-[d-Trp(8)]SRIF (6) was potent and sst(4)-selective (>25-fold); Des-AA(1,2,5,12,13)-[d-Trp(8)]SRIF (7) and Des-AA(1,2,4,5,12,13)-[d-Trp(8)]-SRIF (9, ODT-8) were most potent at sst(4) and moderately potent at all other receptors. Dicyclic SRIF agonists of the sst(1)-selective Des-AA(1,5)-[Tyr(2),d-Trp(8),IAmp(9)]SRIF, (14, sst(1) IC(50) = 14 nM) were prepared in which a lactam bridge introduced additional conformational constraint (IAmp = 4-(N-isopropyl)-aminomethylphenylalanine). Cyclo(7-12)Des-AA(1,5)-[Tyr(2),Glu(7),d-Trp(8),IAmp(9),hhLys(12)]SRIF (31) (sst(1) IC(50) = 16 nM) and cyclo(7-12) Des-AA(1,2,5)-[Glu(7),d-Trp(8),IAmp(9),m-I-Tyr(11),hhLys(12)]SRIF (45) (sst(1) IC(50) = 6.1 nM) had equal or improved affinities over that of the parent 14. Binding affinity was decreased in all other cases with alternate bridging constraints such as cyclo (6-11), cyclo (6-12), and cyclo (7-11). Compound 45 is an agonist (EC(50) = 8.8 nM) in the adenylate cyclase assay.
Rivier
Jean E
JE
The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, 10010 N. Torrey Pines Road, La Jolla, California 92037, USA. Jrivier@salk.edu
Kirby
Dean A
DA
Erchegyi
Judit
J
Waser
Beatrice
B
Eltschinger
Véronique
V
Cescato
Renzo
R
Reubi
Jean Claude
JC
D000818:Animals; D016466:CHO Cells; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017481:Receptors, Somatostatin / Q000819:agonists*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin; C101130:somatostatin receptor type 1; C496955:somatostatin, des-amino acid(1,2,5)-Glu(7)-Trp(8)-IAmp(9)-m-I-Tyr(11)-hhLys(12)-; D005576:Colforsin; D013004:Somatostatin; D000242:Cyclic AMP