title: Anti-secretory properties of non-peptide somatostatin receptor agonists in isolated rat colon: luminal activity and possible interaction with P-glycoprotein.
abstract: 1. The diverse physiological actions of somatostatin are mediated by a family of G-protein coupled receptors (SSTRs). Several peptide analogues of somatostatin such as octreotide have been developed for therapeutic use, including treatment of gastrointestinal disorders such as secretory diarrhoea. However, their development as anti-diarrhoeal agents has been limited by poor oral bioavailability, necessitating parenteral administration. This in vitro study investigated the anti-secretory potential of a group of novel, non-peptide, somatostatin-receptor agonists that selectively activate specific SSTR subtypes to assess their potential for oral administration. 2. The ability of the agonists to inhibit forskolin-stimulated chloride secretion was measured using a sensitive bioassay system in isolated rat colonic mucosa. 3. The SSTR-2 selective agonist, L-779,976 was 10-times more potent than octreotide as an inhibitor of secretion when added to the basolateral surface of rat colon. Non-peptide agonists selective for SSTR1 (L-797,591), SSTR3 (L-796,778), SSTR4 (L-803,087) or SSTR5 (L-817,818) showed little or no anti-secretory activity in this preparation. 4. L-779,976 was able to inhibit secretion when applied to the luminal surface at sub-micromolar concentrations suggesting that it can cross the colonic epithelium. The anti-secretory potency of luminal L-779,976 was increased 3 fold in the presence of GF120918, a known inhibitor of P-glycoprotein. 5. Non-peptide somatostatin receptor agonists may provide a basis for the development of new, orally available anti-diarrhoeal therapies.
authors.affiliation: Gut Barrier and Drug Absorption Group, Clinical Division I, Salford Royal Hospitals NHS Trust & University of Manchester, Clinical Sciences Building, Hope Hospital, Salford M6 8HD, UK.
authors.forename: P T J
authors.initials: PT
authors.lastname: Emery
authors.forename: N B
authors.initials: NB
authors.lastname: Higgs
authors.forename: A C
authors.initials: AC
authors.lastname: Warhurst
authors.forename: G L
authors.initials: GL
authors.lastname: Carlson
authors.forename: G
authors.initials: G
authors.lastname: Warhurst
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000166:Acridines / Q000494:pharmacology; D000577:Amides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000819:agonists* / Q000378:metabolism; D044005:Tetrahydroisoquinolines
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D000577:Amides; D007211:Indoles; D007546:Isoquinolines; C121854:L 779976; D017481:Receptors, Somatostatin; D044005:Tetrahydroisoquinolines; C093733:somatostatin receptor 2; C083501:Elacridar