Human Somatostatin Receptor Specificity of Backbone-Cyclic Analogues Containing Novel Sulfur Building Units

• Published in: Journal of medicinal chemistry Vol. 45; no. 8; pp. 1665 - 1671
• Main Authors: Gazal, Sharon, Gelerman, Garry, Ziv, Ofer, Karpov, Olga, Litman, Pninit, Bracha, Moshe, Afargan, Michel, Gilon, Chaim
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.04.2002; Amer Chemical Soc
• Subjects: Animals; Biological and medical sciences; Chemistry, Medicinal; CHO Cells; Cloning, Molecular; Cricetinae; Disulfides - chemistry; Drug Stability; Humans; In Vitro Techniques; Kidney - metabolism; Life Sciences & Biomedicine; Liver - metabolism; Medical sciences; Molecular Conformation; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Peptides, Cyclic - metabolism; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Radioligand Assay; Rats; Receptors, Somatostatin - metabolism; Science & Technology; Somatostatin - analogs & derivatives; Somatostatin - chemistry; Structure-Activity Relationship; CYSTINE-PEPTIDES; OXIDATION; MOLECULAR-DYNAMICS; CONFORMATION; RELEASE; CYSTEINE-PEPTIDES; DISULFIDE; AGONISTS; CYCLIZATION; SUBSTANCE-P ANALOGS; Molecular rigidity; sst5 somatostatin receptor; Cyclic peptides; Steric hindrance; Selectivity; In vitro; Hydrolysis resistance; Biological fixation; Structure activity relation; Disulfide bond; Peptide synthesis; Somatostatin; Chemical synthesis; sst2 somatostatin receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0100281

Somatostatin-14 (somatostatin) and its clinically available analogues octreotide, lanreotide, and vapreotide are potent inhibitors of growth hormone, insulin, and glucagon release. Recently, a novel backbone cyclic somatostatin analogue c(GABA-Phe-Trp-(D)Trp-Lys-Thr-Phe-GlyC3-NH2) (analogue 1, PTR 3173) that possesses in vivo endocrine selectivity was described. This long-acting octapeptide exhibits high affinity to human recombinant somatostatin receptors (hsst) hsst2, hsst4, and hsst5. Its novel binding profile resulted in potent in vivo inhibition of growth hormone but not of insulin release. We report the synthesis, bioactivity, and structure−activity relationship studies of compounds related to 1. In these analogues, the lactam bridge of 1 was replaced by a backbone disulfide bridge. We present a novel approach for conformational constraint of peptides by utilizing sulfur-containing building units for on-resin backbone cyclization. These disulfide backbone cyclic analogues of 1 showed significant metabolic stability as tested in various enzyme mixtures. Receptor binding assays revealed different receptor selectivity profiles for these analogues in comparison to their prototype. It was found that analogues of 1, bearing a disulfide bridge, had increased selectivity to hsst2 and hsst5; however, they exhibited weaker affinity to hsst4 as compared to 1. These studies imply that ring chemistry, ring size, and ring position of the peptide template may affect the receptor binding selectivity.