Chemical syntheses and biological studies on dimeric chimeras of oxytocin and the V2-antagonist, d(CH2)5[D-Ile2,Ile4]arginine vasopressin

Lin Chen, Regina Golser, Alena Machová, Jirina Slaninová, George Barany

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3 Scopus citations

Abstract

Parallel and antiparallel heterodimers have been synthesized that combine into a single molecule the neurohypophyseal hormone oxytocin and the potent vasopressin V2-antagonist d(CH2)5[D-Ile2,Ile4]arginine vasopressin. Solid-phase synthesis with N(α)-9-fluorenylmethyloxycarbonyl (Fmoc) chemistry, featuring appropriate combinations of orthogonal protecting groups for the thiols [S-(N-methyl-N-phenylcarbamoyl)sulfenyl (Snm); S- acetamidomethyl (Acm); S-triphenylmethyl (Trt)], was used to assemble the required linear nonapeptide amide monomer intermediates, which were then brought together in defined ways by solution reactions to provide the two heterodimers. The first disulfide bridge was formed by a directed approach involving attack by the free thiol of the 1-β-mercapto-β,β- cyclopentamethylenepropionic acid (Pmp) residue of one monomer onto the Snm group of a cysteine residue on the other monomer; the inverse directed strategy failed due to steric hindrance. The second disulfide bridge was formed by iodine co-oxidation of Cys(Acm) residues on adjacent chains. Biological studies revealed that both the parallel and antiparallel chimeras lack pressor activity, have low uterotonic activity, and have diuretic activities comparable to that of the monomeric V2-antagonist. Sodium excretion depends on experimental conditions. Thus, with a 4% water load, both chimeras display effects similar to that of an equimolar mixture of oxytocin and V2-antagonist, i.e., lower sodium excretion than that resulting from administration of oxytocin alone but higher than that when V2- antagonist was administered alone. However, when no water load was used, the parallel chimera proved to be more effective in promoting sodium excretion than either oxytocin alone or an equimolar mixture of oxytocin and V2- antagonist.

Original languageEnglish (US)
Pages (from-to)5002-5009
Number of pages8
JournalJournal of medicinal chemistry
Volume42
Issue number24
DOIs
StatePublished - Dec 2 1999

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