Enantiopure heterocyclic Boc-protected Phe-Gly dipeptidomimetics containing 1,3,4-oxadiazole, 1,2,4-oxadiazole, and 1,2,4-triazole ring systems have been synthesized as building blocks in the synthesis of pseudopeptides. Three derivatives (1-3) have the carboxylic acid function directly bound to the heterocyclic ring, and three derivatives (4-6) have an extra methylene group between the heterocyclic ring and the acid function to allow for an increased conformational flexibility. The mimetics were used as Phe-Gly replacements in the biologically active peptides dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH(2)) and substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-MetNH(2), SP). The pseudopeptide synthesis was performed using solid-phase methodology on a MBHA-resin using Boc-chemistry. The biological evaluation was performed by testing the micro- and delta-opioid receptor affinities of the dermorphin pseudopeptides and the NK(1) receptor affinities of the SP pseudopeptides. The results showed that all mimetics except 3 were excellent replacements of Phe-Gly in dermorphin since they displayed affinities for the micro-receptor (IC(50) = 12-31 nM) in the same range as dermorphin itself (IC(50) = 6.2 nM). The agonist activity of three pseudopeptides at human micro-receptors was also evaluated. It was shown that the tested compounds retained their agonist activity. The SP pseudopeptides showed considerably lower affinities (IC(50) > 1 microM) for the NK(1) receptor than SP itself (IC(50) = 1.5 nM) indicating that the Phe-Gly replacements prevent the pseudopeptides from adopting bioactive conformations.
This chapter focuses on the isosteric replacement of peptide bonds with three different types of heterocyclic ring systems (1); 1,2,4-oxadiazole (2), 1,3,4-oxadiazole (3), and 1,2,4-triazole rings (4-6). The ring systems are similar in size and shape but show variations in aromatic, electrostatic, and hydrogen bonding properties. These variations provide opportunities to study properties of importance for amide bond mimicry. The derivatives are synthesized from protected natural amino acids, and the reaction conditions have been chosen so that the enantiopurity is retained during the reaction sequences. Two series of mimetics will be described, one in which the carboxylic acid functionality is directly attached to the heterocyclic ring (1) and one series with a methylene group inserted between the ring and the carboxylic acid group (7). Since we have focused on the design and synthesis of Phe-Gly mimetics, the synthetic examples described here start from L: -phenylalanine. However, we have used the same synthetic scheme also for other amino acids and notes will be given when other derivatives require differences in reaction conditions (1). The use of the dipeptidomimetics as building blocks in pseudopeptide synthesis will also be described (7). These syntheses are performed on solid phase using Boc-chemistry. Also, the deprotection and purification of the pseudopeptides by reversed phase HPLC will be discussed.
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