Synthesis and properties of analogues of vasopressin with 1-aminocyclopropane-1-carboxylic acid in position 9

Abstract

Dedicated 10 the 1l1f!lIwry of Dr Karel BhiIUl.Solid phase methodology all bcnzhydryluminc resin was used for the synthesis of three analogues of vasopressin with non-ceded amino ucid.1 -uminocyclopropunc-l-carbcxylic acid, in position 9. Two analogues oflysine-vuscprcssin ([Lysll, Acc'[vusopressln (I) and Glyr[Lysll. Acc''[vnsopressin (11) and one analogue of arginine-vasopressin ([Arg N, Acc'[vasoprcssln (111) have been synthesized. The dubious value of tile biological activity of [LysN, D-AlalJlvusopressin was reevaluated and [Lys'', L-Alu'Jlvusoprcssin wus also synthesized and tested for the comparlscu. Differences in solution conformation of these two unulogucs were studied by 11-1 and DC NMR spectroscopy. Biological activities of all analogues were either significantly lowered or almost completely eliminated. Analogues 1-111 were found to be completely inactive in analgesia and the eNS activities tested (active and passive avoidance).During the years of structure-activity studies, the extent of attention devoted to different positions in the peptide chain of vasopressin varied. As far as the position 9 is concerned, even though some analogues modified in this position

Natural Occurrence, Syntheses, and Applications of Cyclopropyl-Group-Containing α-Amino Acids. 1. 1-Aminocyclopropanecarboxylic Acid and Other 2,3-Methanoamino Acids

“…[198][199][200][201][202] Incorporation of ACC in position 9 in nonapeptides derived from lysine-or argininevasopressin furnished selectively acting antidiuretic agonists 116 (Figure 4), but with low potency and no effect on the central nervous system (CNS). 203 ACC was also introduced into the tetrapeptide Tuftsin, substituting the threonine and/or the proline moiety, 204 and into the epidermal growth factor (EGF) sequence 33-42, 205 yet the biological activity of these analogues 117 and 118 (Figure 4) has not been described.…”

“…The discovery that l-aspartyl-l-phenylalanine methyl ester has a very sweet taste has led to numerous investigations of aspartyl peptides as potential artificial sweeteners. Intensive research in the area of 1-aminocyclopropanecarboxylic acid esters as dipeptide sweeteners determined numerous l-aspartyl-1-aminocyclopropanecarboxylic acid esters 111 (Figure ) to have a sweet taste of up to 300 times stronger than that of sucrose. −

4 Additional ACC-containing peptides. −

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“…Figure 4. Additional ACC-containing peptides [193][194][195][196][197][198][199][200][201][202][203][204][205]. …”