title: Modulation of receptor and receptor subtype affinities using diastereomeric and enantiomeric monosaccharide scaffolds as a means to structural and biological diversity. A new route to ether synthesis.
abstract: We show that carbohydrates constitute an attractive source of readily available, stereochemically defined scaffolds for the facile attachment of side chains contained in genetically encoded and other amino acids. beta-D- and beta-L-glucose, L-mannose, and the 6-deoxy-6-N-analogue of beta-D-glucose have been employed to synthesize peptidomimetics that bind the SRIF receptors on AtT-20 mouse pituitary cells, five cloned human receptor subtypes (hSSTRs), and the NK-1 receptor. The affinity profile of various sugar-based ligands at the hSSTRs is compared with that of SRIF. Compound 19 bound hSSTR4 with a Ki of 100 nM. Subtle structural changes affect affinities. Evidence is presented that suggests that one compound (8) binds both the AtT-20 cell receptors and the five hSSTRs via a unique mode. The SARs of the glycosides at SRIF receptors differ markedly from those at the NK-1 receptor. For example a 4-benzyl substituent is important for SRIF receptor binding, but the 4-desbenzyl analogue 27 was highly potent (IC50 of 27 nM) at the NK-1 receptor. A new, nonbasic method for the synthesis of base-sensitive ethers from primary and secondary alcohols is also described.
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: R
authors.initials: R
authors.lastname: Hirschmann
authors.forename: J
authors.initials: J
authors.lastname: Hynes
authors.forename: M A
authors.initials: MA
authors.lastname: Cichy-Knight
authors.forename: R D
authors.initials: RD
authors.lastname: van Rijn
authors.forename: P A
authors.initials: PA
authors.lastname: Sprengeler
authors.forename: P G
authors.initials: PG
authors.lastname: Spoors
authors.forename: W C
authors.initials: WC
authors.lastname: Shakespeare
authors.forename: S
authors.initials: S
authors.lastname: Pietranico-Cole
authors.forename: J
authors.initials: J
authors.lastname: Barbosa
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: W
authors.initials: W
authors.lastname: Yao
authors.forename: S
authors.initials: S
authors.lastname: Rohrer
authors.forename: A B
authors.initials: AB
authors.lastname: Smith
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D005960:Glucosides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D018716:Molecular Mimicry; D009005:Monosaccharides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000819:agonists*; D013004:Somatostatin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C111908:2,3,4,5,6-pentadeoxy-6-((5-aminopentyl)oxy)-2,3,4-tribenzoxy-2-methoxyglucose; D004987:Ethers; D005960:Glucosides; D008024:Ligands; D009005:Monosaccharides; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D018040:Receptors, Neurokinin-1; D017481:Receptors, Somatostatin; C040704:cyclo(Pro-Phe-Trp-Lys-Thr-Phe); D013004:Somatostatin; D008239:Lysine