Utilizing NNC 26-9100 (11) as a structural lead, a variety of nonpeptide derivatives of somatostatin were synthesized and evaluated for sst2 and sst4 receptor binding affinity. A novel thiourea scaffold was utilized to attach (1) a heteroaromatic nucleus to mimic the Trp8 residue, (2) a nonheteroaromatic nucleus to mimic Phe7, and (3) a primary amine or other basic group to mimic the Lys9 residue of somatostatin. Displacement studies were carried out using membranes from cell lines expressing ssts [BHK cells (sst4) and HEK 293 cells (sst2)] utilizing [125I]Tyr11-SRIF as the radioligand. Several thioureas (11, 38, 39, 41, and 42) and the urea 66 exhibited Ki values of less than 100 nM. The thioureas 11 (Ki = 6 nM) and 41 (Ki = 16 nM) and the urea 66 (Ki = 14 nM) are believed to be the most potent nonpeptide sst4 agonists known. Since the thiourea 11 and the urea 66 exhibit high sst4 selectivity, these novel nonpeptide derivatives may be useful tools for studying the sst4 receptor. Studies are currently in progress to evaluate the therapeutic potential of NNC 26-9100 (11) in the treatment of glaucoma.
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ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Somatostatin [somatotropin release-inhibiting factor (SRIF)] is a cyclic tetradecapcptiJc that is a potent inhibitor of growth hormone (GH) secretion from the anterior pituitary. In addition to the inhibitory effects on GH-release, SRIF-14 and SRJF-28, a 28-amino acid form of SRIF extended from the N-terminal end, inhibit the release of a variety of other peptides including glucagon, insulin, and gastriri, and both peptides act as neurotransmitters and neuromodulators in the central nervous system and the periphery. SRIF exerts its potent inhibitory effects following binding to high affinity SRIF receptors (ssts) that have been identified on target tissues. The recent cloning of five ssts has confirmed that the effects of SRIF are mediated by a family of G protein-coupled receptors (sst1-5). Based on structural and pharmacological properties sst2, sst3, and sst5 belong to the SRIF1 receptor subclass, and the sst1 and sst4 subtypes comprise the SRIF2 subclass. The major difference between these two subclasses is that SRIF1 receptors bind octapeptide and hexapeptide SRIF-14 analogs with high affinity, while SRIF2 receptors bind these analogs with drastically reduced affinity.
A screening program was initiated to identify a lead nonpeptide with affinity for sst1-5 receptors. The search focused on a scaffold with the following attachments: (I) a heteroaromatic nucleus to mimic the Trp8 residue, (2) a nonheteroaromatic nucleus to mimic Phe7, and (3) a primary amine or other basic group to mimic the Lys9
residue of SRIF-14. Using these criteria, a novel thiourea (NNC 26-9100, 17) was discovered as a structural lead. The key fragments in this compound are a heteroaromatic moiety (pyridine), an aromatic group, and a basic imidazole group connected through a thiourea scaffold. Compound 17 exhibited a Ki = 6 nM at sst4 receptors with a JOO-fold sst4/sst2 selectivity and was shown to be a full agonist at this receptor subtype. This article will review the literature on the design and development of nonpeptide somatostatin receptor ligands and the therapeutic potential of these agents. Furthermore, our work on the development of 2-pyridylthioureas as sst4 receptor agonists will be described.
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