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 (sst1) selective scaffolds. Des-AA ,,, -[d-Trp8]SRIF (2) retained high binding affinity at all receptors but sst1, Des-AA1,2,4,5-[d-Trp8]SRIF (3) at sst4 and sst5, and Des-AA1,2,4,5,13-[d-Trp8]SRIF (4) at sst2 and sst4 (AA = amino acid). Des-AA1,2,4,12,13-[d-Trp8]SRIF (6) was potent and sst4-selective (>25-fold); Des-AA1,2,5,12,13-[d-Trp8]SRIF (7) and Des-AA1,2,4,5,12,13-[d-Trp8]-SRIF (9, ODT-8) were most potent at sst4 and moderately potent at all other receptors. Dicyclic SRIF agonists of the sst1-selective Des-AA1,5-[Tyr2,d-Trp8,IAmp9]SRIF, (14, sst1 IC50 = 14 nM) were prepared in which a lactam bridge introduced additional conformational constraint (IAmp = 4-(N-isopropyl)-aminomethylphenylalanine). Cyclo(7−12)Des-AA1,5-[Tyr2,Glu7,d-Trp8,IAmp9,hhLys12]SRIF (31) (sst1 IC50 = 16 nM) and cyclo(7−12) Des-AA1,2,5-[Glu7,d-Trp8,IAmp9,m-I-Tyr11,hhLys12]SRIF (45) (sst1 IC50 = 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 (EC50 = 8.8 nM) in the adenylate cyclase assay.