Discovery of a Novel Non-Peptide Somatostatin Agonist with SST₄ Selectivity

Abstract

The discovery of novel non-peptide compounds with a high affinity for the peptide hormone somatostatin (SST) receptor is described. The compounds were tested for affinity at five human SST receptor subtypes individually expressed in mammalian cells. The compound NNC 26-9100 showed a K i of 6 nM at SST 4 and more than 100 fold selectivity for SST 4 over SST 1 , SST 2 , SST 3 , or SST 5 . Competition binding studies and Scatchard analysis of the interaction by NNC 26-9100 with SST showed specificity at SST 4 . Furthermore, NNC 26-9100 was highly selective for SST 4 over a variety of other G protein-coupled receptors, having affinities for M 1 muscarinic acetylcholin and D 3 dopamine receptors of around 500 and 1000 nM, respectively. Finally, NNC 26-9100 was found to fully inhibit forskolin-induced accumulation of adenosine 3′,5′-cyclic monophosphate in baby hamster kidney cells, expressing the human SST 4 receptor with an EC 50 of 2 nM.

Somatostatin receptor subtype-4 agonist NNC 26–9100 decreases extracellular and intracellular Aβ1–42 trimers

“…A.M. Crider per previously established protocols (Ankersen et al, 1998; Crider et al, 2004). All other chemicals and reagents, unless otherwise stated, were purchased from Sigma-Aldrich (St. Louis, MO).…”

“…Not only are the cortex and hippocampus areas vital to learning and memory, but are also significantly affected by Aβ accumulation and associated with reduced neprilysin levels in Alzheimer’s disease patients (Yasojima et al, 2001a; Yasojima et al, 2001b). The SSTR4 agonist NNC 26-9100 is an enzymatically stable non-peptide drug having a >100-fold selectivity for SSTR4 over other subtypes (Ankersen et al, 1998; Crider et al, 2004). We have previously shown that chronic (i.p.)…”

Chronic peripheral administration of somatostatin receptor subtype-4 agonist NNC 26-9100 enhances learning and memory in SAMP8 mice

“…1) is a highly selective and high affinity sst4 receptor agonist, with >100-fold selectivity for sst4 over all other somatostatin receptor subtypes (K i = 6 nM) (Ankersen et al, 1998; Crider et al, 2004). To determine the ability of NNC 26-9100 to appropriately distribute to the brain we assessed brain uptake of radioactively labeled NNC 26-9100 via jugular vein injection (mouse), as well as regional distribution to critical brain areas associated with Alzheimer's disease.…”

Small-molecule agonists for the glucagon-like peptide 1 receptor

“…In recent years, smallmolecule agonists have been described, even for receptors for larger hormones like insulin, TPO, and EPO (18)(19)(20), but none of these receptors belong to the GPCR superfamily. Within the GPCRs, small-molecule agonists have been described, e.g., for the arginine vasopressin V-2 receptor, the somatostatin receptor, the bradykinin receptor, the cholecystokinin receptor, the angiotensin II receptor, and the growth hormone secretagogue receptor (21)(22)(23)(24)(25)(26). However, none of these GPCRs belong to the B family, and the natural ligands are all either fairly small or have a defined secondary structure.…”