Synthesis and biological activities of arginine-vasopressin analogs designed from a conformation-activity approach

Abstract

Using the proposed conformation of vasopressin thought to be preferred when the mammalian antidiuretic hormone is bound to its renal receptor, an analogue, [1-d-mercaptopropionic acid,2-phenylalanine,7-(3,4-dehydroproline) ] arginine-vasopressin, was designed that contained three synthetic modifications. It posessed a rat antidiuretic potency of 13000 ± 1250 units/mg, no measurable rat pressor activity, an in vitro rat uterotonic potency of 6.0 ± 0.6 units/mg, and an avian vasodepressor potency of 2.9 ± 0.5 units/mg. The strong dissociation of an apparently very high antidiuretic activity of this analogue from its other biological activities prompted the synthesis of the singly and doubly modified analogues of this series of 3,4-dehydroproline-containing derivatives. ]arginine-vasopressin, [ 2-phenylalanine,7 -(3,4-dehydroproline) ] arginine-vasopressin, and [7-(3,4-dehydroproline)]arginine-vasopressin were found to have the following specific activities (units/mg), respectively:

Rotational Barriers ofcis/transIsomerization of Proline Analogues and Their Catalysis by Cyclophilin

“…Proline derivatives are often incorporated into biologically active peptides to study conformational effects − or to increase the bioavailibility because the unique cyclic structure restricts the attack of proteases. , While 4-Thz was often incorporated into collagen model compounds 26,27 or bioactive molecules such as thrombin inhibitors, somatostatin 20,28 dipeptidyl peptidase IV substrates, angiotensin II, angiotensin converting enzyme inhibitors, and oxytocin, 4-Oxa residues are rarely used 17,29 because of the acid lability of the oxazolidine ring and the related synthetic difficulties. On the basis of X-ray studies of N -acetylthiazolidine-4-carboxamide and theoretical calculations of polythiazolidine-4-carboxylic acid and polyoxazolidine-4-carboxylic acid, it was suggested that, in contrast to poly-Pro and poly-4-Oxa, poly-4-Thz should not mutarotate from trans to the cis form in helical structures. , Piperidine-2-carboxylic acid (Pip) has been incorporated into analogues of bioactive peptides, such as bradykinin, angiotensin II, oxytocin, angiotensin converting enzyme inhibitors, thrombin substrates, and inhibitors .…”

“…Proline derivatives are often incorporated into biologically active peptides to study conformational effects [16][17][18][19][20][21][22][23] or to increase the bioavailibility because the unique cyclic structure restricts the attack of proteases. 24,25 While 4-Thz was often incorporated into collagen model compounds 26,27 or bioactive molecules such as thrombin inhibitors, 18 somatostatin 20,28 IV substrates, 29 angiotensin II, 30 angiotensin converting enzyme inhibitors, 17 and oxytocin, 31 4-Oxa residues are rarely used 17,29 because of the acid lability of the oxazolidine ring and the related synthetic difficulties.…”

Conformational selection of vasopressin upon V1a receptor binding

“…At the same time, the C-terminal tail modulates binding affinities via a few intermolecular contacts [66] . Indeed, SAR studies of VP revealed that modification or replacement of Pro 7 in VP can affect V 1a /V 2 receptor selectivity [67] , [68] .…”

Design and Synthesis of a 3,4-Dehydroproline Amide Discovery Library

“… The synthesis of a discovery library of 80 3,4-dehydroproline amides was achieved in a four-step reaction sequence from easily accessible 3-aminoallene-3-carboxylate methyl esters. Diversification of these proline mimics was introduced at five different sites: the substituents at the 3-pyrroline unit (R, R, R), at the nitrogen (R), and the C -terminus (R). The 3-pyrroline scaffold was synthesized in excellent yields by a silver-catalyzed intramolecular cyclization of aminoallenes, followed by N -functionalization reactions.…”