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

J Med Chem. 1998 Apr 23;41(9):1382-91. doi: 10.1021/jm9800346.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • CHO Cells
  • Cell Line
  • Cricetinae
  • Ethers / chemical synthesis
  • Ethers / chemistry
  • Ethers / metabolism*
  • Glucosides / chemical synthesis
  • Glucosides / chemistry
  • Glucosides / metabolism*
  • Humans
  • Ligands
  • Lysine / metabolism
  • Mice
  • Models, Molecular
  • Molecular Mimicry*
  • Monosaccharides / chemical synthesis
  • Monosaccharides / chemistry
  • Monosaccharides / metabolism*
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism
  • Pituitary Gland / cytology
  • Pituitary Gland / metabolism
  • Receptors, Cell Surface / metabolism*
  • Receptors, Neurokinin-1 / metabolism
  • Receptors, Somatostatin / agonists*
  • Somatostatin / analogs & derivatives
  • Somatostatin / chemistry
  • Somatostatin / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • 2,3,4,5,6-pentadeoxy-6-((5-aminopentyl)oxy)-2,3,4-tribenzoxy-2-methoxyglucose
  • Ethers
  • Glucosides
  • Ligands
  • Monosaccharides
  • Peptide Fragments
  • Receptors, Cell Surface
  • Receptors, Neurokinin-1
  • Receptors, Somatostatin
  • cyclo(Pro-Phe-Trp-Lys-Thr-Phe)
  • Somatostatin
  • Lysine