Somatostatin Receptor 1 Selective Analogues:  2. Nα-Methylated Scan

• Published in: Journal of medicinal chemistry 2005-01, Vol.48 (2), p.507-514
• Main Authors: Erchegyi, Judit, Hoeger, Carl A, Low, William, Hoyer, Daniel, Waser, Beatrice, Eltschinger, Véronique, Schaer, Jean-Claude, Cescato, Renzo, Reubi, Jean Claude, Rivier, Jean E
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049520l

Des-AA ,, -[d-Trp8/d-Nal8,IAmp9]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 (sst1 - 5). Nα-Methylation resulted in loss of sst affinity (2- to >5-fold) when introduced at residues Lys4 (6), Phe6 (7), Phe7 (8), Thr10 (11), and Phe11 (12) of the parent compound Des-AA1,2,5-[d-Nal8,IAmp9]SRIF (4). Nα-Methylation was tolerated at residues Cys (5), d-Nal8 (9), Thr12 (13), and Cys14 (15) with retention of binding sst affinity and selectivity and resulted in an increase in sst binding affinity at positions IAmp9 (10) and Ser13 (14). In these series, the d-Trp8 substitution versus d-Nal8 is clearly superior. C-Terminally lysine-extended analogues (21−25) retained sst1 selectivity and binding affinity when compared to their d-Nal8- (4) or d-Trp8- (3) containing parent. Des-AA1,2,5-[d-Trp8, (N αMe)IAmp9]SRIF (17), Des-AA1,2,5-[d-Trp8,IAmp9,(N αMe)Ser13]SRIF (19), Des-AA1,2,5-[d-Trp8,IAmp9,(N αMe)Cys14]SRIF (20), Des-AA1,2,5-[d-Trp8,(N αMe)IAmp9,Tyr11]SRIF (34), and Des-AA1,2,5-[d-Agl8(N βMe,2-naphthoyl),IAmp9,Tyr11]SRIF (42) (Agl = aminoglycine) are sst1 agonists in their ability to inhibit forskolin-induced cAMP production.