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

• Published in: Journal of medicinal chemistry 1998-04, Vol.41 (9), p.1382-1391
• Main Authors: Hirschmann, Ralph, Hynes, John, Cichy-Knight, Maria A, van Rijn, Rachel D, Sprengeler, Paul A, Spoors, P. Grant, Shakespeare, William C, Pietranico-Cole, Sherrie, Barbosa, Joseph, Liu, Josephine, Yao, Wenqing, Rohrer, Susan, Smith, Amos B
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Line; CHO Cells; Cricetinae; Ethers - chemical synthesis; Ethers - chemistry; Ethers - metabolism; Glucosides - chemical synthesis; Glucosides - chemistry; Glucosides - metabolism; Humans; Ligands; Lysine - metabolism; Medical sciences; Mice; Models, Molecular; Molecular Mimicry; Monosaccharides - chemical synthesis; Monosaccharides - chemistry; Monosaccharides - metabolism; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; 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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9800346

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. β-d- and β-l-glucose, l-mannose, and the 6-deoxy-6-N-analogue of β-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 K i 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.