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.

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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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