title: Nonpeptide somatostatin agonists with sst4 selectivity: synthesis and structure-activity relationships of thioureas.
abstract: 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.
authors.affiliation: Division of Basic Pharmaceutical Sciences, School of Pharmacy, Northeast Louisiana University, Monroe, Louisiana 71209-0470, USA.
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.forename: C
authors.initials: C
authors.lastname: Tang
authors.forename: B
authors.initials: B
authors.lastname: Ho
authors.forename: M
authors.initials: M
authors.lastname: Ankersen
authors.forename: C E
authors.initials: CE
authors.lastname: Stidsen
authors.forename: A M
authors.initials: AM
authors.lastname: Crider
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D005901:Glaucoma / Q000188:drug therapy; D006801:Humans; D008565:Membrane Proteins; D011869:Radioligand Assay; D017481:Receptors, Somatostatin / Q000819:agonists* / Q000096:biosynthesis; D013004:Somatostatin / Q000819:agonists*; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000631:Aminopyridines; D008565:Membrane Proteins; C115929:NNC 26-9100; D017481:Receptors, Somatostatin; C098681:somatostatin receptor subtype-4; D013004:Somatostatin; C093733:somatostatin receptor 2; D013890:Thiourea