Design, synthesis, and evaluation of Phe-Gly mimetics: heterocyclic building blocks for pseudopeptides.
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.
Borg
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S
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Centre, Uppsala University, Box 574, S-751 23 Uppsala, Sweden.
Vollinga
R C
RC
Labarre
M
M
Payza
K
K
Terenius
L
L
Luthman
K
K
D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D004151:Dipeptides / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
D004151:Dipeptides; D009842:Oligopeptides; D010069:Oxadiazoles; D018040:Receptors, Neurokinin-1; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D014230:Triazoles; C040500:phenylalanylglycine