title: Somatostatin receptor 1 selective analogues: 2. N(alpha)-Methylated scan.
abstract: Des-AA(1,2,5)-[d-Trp(8)/d-Nal(8),IAmp(9)]SRIF (AA = amino acid, Nal = 3-(2-naphthyl)-alanine, IAmp = 4-(N-isopropyl)-aminomethylphenylalanine, SRIF = somatostatin), with or without a tyrosine or monoiodotyrosine, were scanned with the introduction of a backbone N-methyl group and tested for binding affinity at the five human somatostatin receptors (sst(1)(-)(5)). N(alpha)-Methylation resulted in loss of sst affinity (2- to >5-fold) when introduced at residues Lys(4) (6), Phe(6) (7), Phe(7) (8), Thr(10) (11), and Phe(11) (12) of the parent compound Des-AA(1,2,5)-[d-Nal(8),IAmp(9)]SRIF (4). N(alpha)-Methylation was tolerated at residues Cys(3) (5), d-Nal(8) (9), Thr(12) (13), and Cys(14) (15) with retention of binding sst affinity and selectivity and resulted in an increase in sst binding affinity at positions IAmp(9) (10) and Ser(13) (14). In these series, the d-Trp(8) substitution versus d-Nal(8) is clearly superior. C-Terminally lysine-extended analogues (21-25) retained sst(1) selectivity and binding affinity when compared to their d-Nal(8)- (4) or d-Trp(8)- (3) containing parent. Des-AA(1,2,5)-[d-Trp(8), (N(alpha)Me)IAmp(9)]SRIF (17), Des-AA(1,2,5)-[d-Trp(8),IAmp(9),(N(alpha)Me)Ser(13)]SRIF (19), Des-AA(1,2,5)-[d-Trp(8),IAmp(9),(N(alpha)Me)Cys(14)]SRIF (20), Des-AA(1,2,5)-[d-Trp(8),(N(alpha)Me)IAmp(9),Tyr(11)]SRIF (34), and Des-AA(1,2,5)-[d-Agl(8)(N(beta)Me,2-naphthoyl),IAmp(9),Tyr(11)]SRIF (42) (Agl = aminoglycine) are sst(1) agonists in their ability to inhibit forskolin-induced cAMP production.
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California, 92037, USA.
authors.forename: Judit
authors.initials: J
authors.lastname: Erchegyi
authors.forename: Carl A
authors.initials: CA
authors.lastname: Hoeger
authors.forename: William
authors.initials: W
authors.lastname: Low
authors.forename: Daniel
authors.initials: D
authors.lastname: Hoyer
authors.forename: Beatrice
authors.initials: B
authors.lastname: Waser
authors.forename: Véronique
authors.initials: V
authors.lastname: Eltschinger
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Schaer
authors.forename: Renzo
authors.initials: R
authors.lastname: Cescato
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Jean E
authors.initials: JE
authors.lastname: Rivier
mesh_terms: D000818:Animals; D016466:CHO Cells; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D008745:Methylation; D011869:Radioligand Assay; D017481:Receptors, Somatostatin / Q000819:agonists*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C110576:CH 275; D017481:Receptors, Somatostatin; C101130:somatostatin receptor type 1; D005576:Colforsin; D013004:Somatostatin; D000242:Cyclic AMP