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

We show that carbohydrates constitute an attractive source of readily available, stereochemically defined scaffolds for the facile attachmen t of side chains contained in genetically encoded and other amino acid s. 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 th at bind the SRIF receptors on AtT-20 mouse pituitary cells, five clone d human receptor subtypes (hSSTRs), and the NK-1 receptor. The affinit y profile of various sugar-based ligands at the hSSTRs is compared wit h that of SRIF. Compound 19 bound hSSTR4 with a K-i of 100 nM. Subtle structural changes affect affinities. Evidence is presented that sugge sts 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 rec eptors 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 r eceptor. A new, nonbasic method for the synthesis of base-sensitive et hers from primary and secondary alcohols is also described.