New Analogues Of Arginine Vasopressin Research Articles

Design, Synthesis and Structure–Activity Relationship of New Arginine Vasopressin Analogues Containing Proline Derivatives in Position 2

In this study, we present the synthesis and pharmacological properties of new analogues of arginine vasopressin modified in the N-terminal part of the molecule with proline derivatives: indoline-2-carboxylic acid (Ica) and (2S,4R)-4-(naphthalene-2-ylmethyl)pyrrolidine-2-carboxylic acid. All the peptides were tested for pressor, antidiuretic and in vitro uterotonic activities. We also determined their binding affinity to the human oxytocin receptor. The Ica(2) substitution resulted in two moderately potent and selective antioxytocic agents: [Mpa(1), Ica(2), D-Arg(8)]VP and [Mpa(1),Ica(2),Val(4),D-Arg(8)]VP (pA(2) = 7.09 and 7.50, respectively). On the other hand, peptides modified with (2S,4R)-4-(naphthalene-2-ylmethyl)pyrrolidine-2-carboxylic acid, apart from their moderate antioxytocic activity, turned out to be weak antagonists of the pressor response to arginine vasopressin. The results of this study provide useful information about the structure-activity relationship of arginine vasopressin analogues and can help to design compounds with desired biological properties.

Analogues of arginine vasopressin modified in position 2 or 3 with naphthylalanine: selective antagonists of oxytocin in-vitro.

In this study we describe the synthesis and some pharmacological properties of six new analogues of arginine vasopressin (AVP). Five of the peptides were substituted in position 2 with L-1-naphthylalanine (L-1-Nal) or D-1-naphthylalanine (D-1-Nal); one had D-1-Nal in position 3. All analogues were tested in bioassays for pressor and antidiuretic activity. We also tested the uterotonic activity of the peptides in-vitro. Two of the new peptides were moderately potent V1a and oxytocin antagonists. The modifications proposed resulted in a drop or the removal of antidiuretic activity and in the removal of pressor activity, or conversion into moderate antagonists. Two peptides ([Mpa1, (L-1-Nal)2]AVP and [Mpal, (D-1-Nal)2]AVP) which appear not to interact with V1a and V2 receptors were exceptionally selective oxytocin antagonists in vitro. These compounds with selective oxytocin antagonistic activity may be promising candidates for the development of potential tocolytic agents for the prevention of pre-term labour.

Arginine vasopressin and its analogues – The influence of position 2 modification with 3,3-diphenylalanine enantiomers. Highly potent V 2 agonists

Eleven new analogues of arginine vasopressin (AVP) modified in position 2 by 3,3-diphenyl- l-alanine or its d-enantiomer (Dip or d-Dip) were synthesized and pharmacologically evaluated for their pressor, antidiuretic and in vitro uterotonic activities. Both the Dip and d-Dip modifications at position 2 of AVP are sufficient to completely change the pharmacological profile of the peptides. They preserve or increase antidiuretic activity, cause its prolongation, transform uterotonic property in antagonistic one and cancel the effect on blood pressure. Four of the new peptides ([Mpa 1, d-Dip 2]AVP, [Mpa 1, d-Dip 2,Val 4]AVP, [Mpa 1, d-Dip 2, d-Arg 8]VP, [Mpa 1, d-Dip 2,Val 4, d-Arg 8]VP) are exceptionally potent antidiuretic agents with significantly prolonged activities.

The Effects of N-Terminal Part Modification of Arginine Vasopressin Analogues with 2-Aminoindane-2-carboxylic Acid: A Highly Potent V2Agonist

In this study we present the synthesis and some pharmacological properties of nine new analogues of arginine vasopressin modified in the N-terminal part of the molecule with 2-aminoindane-2-carboxylic acid (Aic). The peptides were tested for their in vitro uterotonic and in vivo pressor and antidiuretic activities. One of the new peptides, [Mpa1,Aic2,Val4,D-Arg8]VP, exhibited an antidiuretic activity similar to that of [Mpa1,D-Arg8]VP, thus being one of the most potent antidiuretic vasopressin analogues reported to date.

Influence of Conformationally Constrained Amino Acids Replacing Positions 2 and 3 of Arginine Vasopressin (AVP) and Its Analogues on Their Pharmacological Properties

Synthesis of thirteen new analogues of arginine vasopressin (AVP) has been described. Amino acid residues at positions 2 and 3 of AVP, [3-mercaptopropionic acid (Mpa)(1)]AVP (dAVP), [Mpa(1),d-Arg(8)]VP (dDAVP) and [Mpa(1),Val(4),d-Arg(8)]VP (dVDAVP) were replaced with one amino acid residue using sterically constrained non-proteinogenic amino acids, 4-aminobenzoic acid (Abz), cis-4-aminocyclohexanecarboxylic acid (ach) or its trans-isomer (Ach). In the case of a potent V(1a) antagonist, [1-mercaptocyclohexaneacetic acid (Cpa)(1)]AVP, only one similar analogue has been prepared by replacing positions 2 and 3 with Abz. Unfortunately, all new peptides were inactive in bioassays for the pressor, antidiuretic and uterotonic in vitro activities in the rat.

Analogs of arginine vasopressin modified in the N‐terminal part of the molecule with a conformationally constrained cis‐peptide bond motif

The present work is part of our studies aimed at clarifying the influence of steric constraints in the N-terminal part of arginine vasopressin (AVP) and its analogs on the pharmacological activity of the resulting peptides. We describe the synthesis of eight new analogs of AVP or [3-mercaptopropionic acid (Mpa)]AVP (dAVP) substituted at positions 2 and 3 or 3 and 4 with two diastereomers of 4-aminopyroglutamic acid. The steric constraints provided by this modification turned out, however, so strong that all the peptides were inactive in all of the bioassays (pressor, antidiuretic and uterotonic tests).

The influence of 1-aminocyclopentane-1-carboxylic acid at position 2 or 3 of AVP and its analogues on their pharmacological properties

This study describes the synthesis and some pharmacological properties of eight new analogues of arginine vasopressin (AVP) substituted at position 2 or 3 with cycloleucine (1-aminocyclopentane-1-carboxylic acid, Apc). All new peptides were tested for their pressor, antidiuretic and uterotonic in vitro potency. The Apc3 modification resulted in an almost complete loss of potency in all three tests, which is interpreted as a loss of interaction with all three neurohypophyseal hormone receptors. On the other hand, the Apc2 modification resulted in compounds having differently modified activities (high antidiuretic potency, low and graded pressor activity and either no activity or low oxytocin antagonizing activity in the uterotonic in vitro test) thus selectively altering the interaction with the receptors similar to that of 1-aminocyclohexane-1-carboxylic acid (Acc). The results obtained may be helpful for designing new analogues of arginine vasopressin.

Influence of enantiomers of 1-naphthylalanine in position 2 of VAVP and dVAVP on their pharmacological properties

In this study, we described the synthesis and some pharmacological properties of four new analogues of arginine vasopressin (AVP). Two peptides are substituted in position 2 with l-1-naphthylalanine ( l-1-Nal) or its d-enantiomer and in position 4 with valine. In the further two compounds, we combined the above modifications with placement into position 1 of 3-mercaptopropionic acid residue (Mpa). All new peptides were tested for vasopressor and antidiuretic activities. We also estimated the uterotonic activities of these compounds in vitro. Urine samples prior and after peptide administration were analyzed for electrolytes excretion. All analogues are potent oxytocin antagonists. One of them, namely [ l-1-Nal 2,Val 4]AVP, which appears practically not to interact with V 1a and V 2 receptors, is exceptionally selective. Our results open new possibilities for the design of very potent and selective oxytocin antagonists in vitro.

Analogues of arginine vasopressin modified in position 2 and 3 with conformationally constrained dipeptide fragments

This study describes the synthesis and some pharmacological properties of ten new analogues of arginine vasopressin (AVP) containing a conformationally constrained dipeptide fragment in the N-terminal part of their molecules. Amino acid residues in positions 2 and 3 of AVP and some of its agonistic analogues were replaced with -Phe-Phe and D-Phe-D-Phe, dipeptides having a -CH2-CH2- link bridging two nitrogens. All the new peptides were tested for vasopressor and antidiuretic activities. Four peptides with pA2 values ranging from 5.96 to 7.21 turned out to be weak or moderately potent V1a antagonists. The results supplied new information about the structure-activity relationship of AVP analogues. As some of these were unexpected, they point to the need for caution when extrapolating previously known effects of modifications to analogues having conformationally constrained fragments in their molecules.

Analogues of arginine vasopressin modified in the N-terminal part of the molecule with enantiomers of N-methylphenylalanine.

Four new analogues of arginine vasopressin (AVP) substituted in positions 2 and 3 with all possible combinations of enantiomers of N-methylphenylalanine were synthesized and studied to assess the influence of N-methylation of the peptide bonds between the first three amino acids on the pharmacological properties of the resulting peptides. The next three analogues were designed to learn how the shortening of the peptide chain, by removal of one of the N-methylphenylalanine residues, would affect pharmacological properties of the resulting compounds. The activity of the analogues was tested in the in vitro uterotonic, pressor and antidiuretic tests. None of the prepared analogues displayed significant biological activity with the exception of [Me-d-Phe(2), Me-Phe(3)]AVP and [Me-d-Phe(2,3)]AVP, which showed low antiuterotonic activity (pA(2) = 6.6 and pA(2) = 6.4, respectively). Our results, while not impressive in terms of biological activity, may be helpful for designing potent and selective oxytocin antagonists.

Molecular Modeling of Interaction of the Vasopressin Analogs with Vasopressin and Oxytocin Receptors

AbstractIn this study the interaction of seven new analogs of arginine vasopressin (AVP) substituted in position 2 or 3 with 1‐aminocyclohexanecarboxylic acid (Acc) with the vasopressin (VP) and oxytocin (OT) receptors (V1aR, V2R and OTR) is described. All peptides were synthesized and tested in bioassays for pressor and antidiuretic activities. Also their uterotonic activity in vitro has been measured. This work was aimed at checking the applicability of computational methods for predicting receptor‐ligand interactions and makes a good basis for selecting the receptor amino acid residues involved in ligand binding. The results of this study suggest preferred geometries of new, potentially active AVP analogs.

Influence of 1-aminocyclohexane-1-carboxylic acid in position 2 or 3 of AVP and its analogues on their pharmacological properties.

In this study we describe the synthesis and some pharmacological properties of seven new analogues of arginine vasopressin (AVP) substituted in position 2 or 3 with 1-aminocyclohexane-1-carboxylic acid (Acc). All peptides were tested for the pressor, antidiuretic and uterotonic in vitro activities. The Acc3 modifications of AVP, dAVP, [d-Arg8]VP and [Cpa1]AVP have been found to be deleterious for interaction with all three neurohypophyseal hormone receptors, as judged from the several orders of magnitude decreased biological activities, whereas Acc2 substitution selectively altered the interaction with the receptors. Two of the new analogues, [Acc2]AVP and [Acc2, d-Arg8]AVP, are potent antidiuretic agonists. [Acc2]AVP exhibits moderate pressor agonistic activity and weak antiuterotonic properties. [Acc2, d-Arg8]AVP has been found to be a weak antagonist in the pressor and uterotonic tests. Another analogue - [Cpa1, Acc3]AVP - turned out to be a highly selective V2 agonist. This is an unexpected effect, as its parent peptide, [Cpa1]AVP is a very potent V1a receptor antagonist. This is the first Cpa1 modification to have resulted in V2 agonism enhancement. Besides providing useful information about structure-activity relationships, our results could open up new possibilities in the design of highly potent and selective V2 agonists.

An investigation of position 3 in arginine vasopressin with aliphatic, aromatic, conformationally-restricted, polar and charged amino acidsSymbols and abbreviations are in accordance with the recommendations of the IUPAC-IUB Commission on Biochemical Nomenclature (Eur. J. Biochem. 180, A9-A11, 1989).

We report the solid-phase synthesis and some pharmacological properties of 23 new analogs of arginine vasopressin (AVP) which have the Phe3 residue replaced by a broad variety of amino acids. Peptides 1–9 have at position 3: (1) the mixed aromatic/aliphatic amino acid thienylalanine (Thi) and the aliphatic amino acids; (2) cyclohexylalanine (Cha); (3) norleucine (Nle); (4) Leu; (5) norvaline (Nva); (6) Val; (7) alpha-aminobutyric acid (Abu); (8) Ala; (9) Gly. Peptides 10–23 have at position 3: the aromatic amino acids, (10) homophenylalanine (Hphe); (11) Tyr; (12) Trp; (13) 2-naphthylalanine (2-Nal); the conformationally-restricted amino acids (14) Pro; (15) 2-aminotetraline-2-carboxylic acid (Atc); the polar amino acids (16) Ser; (17) Thr; (18) Gln; and the charged amino acids (19) Asp; (20) Glu; (21) Arg; (22) Lys; (23) Orn. All 23 new peptides were evaluated for agonistic and, where appropriate, antagonistic activities in in vivo antidiuretic (V2-receptor) and vasopressor (V1a-receptor) assays and in in vitro (no Mg2+) oxytocic assays. The corresponding potencies (units/mg) in these assays for AVP are: 323±16; 369±6 and 13.9±0.5. Peptides 1–9 exhibit the following potencies (units/mg) in these three assays: (1) 379±14; 360±9; 36.2±1.9; (2) 294±21; 73.4±2.7; 0.33±0.02; (3) 249±28; 84.6±4.3; 4.72±0.16; (4) 229±19; 21.4±0.6; 2.1±0.2; (5) 134±5; 31.2±0.9; 28.4±0.2; (6) 114±9; 45.3±2.3; 11.3±1.6; (7) 86.7±2.5; 4.29±0.13; 0.45±0.03; (8) 15.5±1.5; 0.16±0.01; ∼0.02; (9) 3.76±0.03; <0.02; in vitro oxytocic agonism was not detected. These data show that the aliphatic amino acids Cha, Nle, Leu, Nva and Val are well-tolerated at position 3 in AVP with retention of surprisingly high levels of antidiuretic activity. Peptides 2–9 exhibit significant gains in both antidiuretic/vasopressor (A/P) and antidiuretic/oxytocic (A/O) selectivities relative to AVP. [Thi3]AVP appears to be a more potent antidiuretic and oxytocic agonist than AVP and is equipotent with AVP as a vasopressor agonist. The antidiuretic potencies of peptides 10–23 exhibit drastic losses relative to AVP. They range from a low of 0.018±0.001 units/mg for the Lys3 analog (peptide 22) to a high of 24.6±4.6 units/mg for the Hphe3 analog (peptide 10). Their vasopressor potencies are also drastically reduced. These range from a low of <0.002 units/mg for peptide 22 to a high of 8.99±0.44 units/mg for the Atc3 analog (peptide 15). Peptides 10–23 exhibit negligible or undetectable in vitro oxytocic agonism. The findings on peptides 10–23 show that position 3 in AVP is highly intolerant of changes with aromatic, conformationally-restricted, polar and charged amino acids. Furthermore, these findings are in striking contrast to our recent discovery that position 3 in the potent V2/V1a/OT antagonist d(CH2)5d-Tyr(Et)2VAVP tolerates a broad latitude of structural change at position 3 with many of the same amino acids, to give excellent retention of antagonistic potencies. The data on peptides 1–4 offer promising clues to the design of more potent and selective AVP V2 agonists. Copyright © 1999 European Peptide Society and John Wiley & Sons, Ltd.

An investigation of position 3 in arginine vasopressin with aliphatic, aromatic, conformationally-restricted, polar and charged amino acids.

We report the solid-phase synthesis and some pharmacological properties of 23 new analogs of arginine vasopressin (AVP) which have the Phe3 residue replaced by a broad variety of amino acids. Peptides 1-9 have at position 3: (1) the mixed aromatic/aliphatic amino acid thienylalanine (Thi) and the aliphatic amino acids; (2) cyclohexylalanine (Cha); (3) norleucine (Nle); (4) Leu; (5) norvaline (Nva); (6) Val; (7) alpha-aminobutyric acid (Abu); (8) Ala; (9) Gly. Peptides 10-23 have at position 3: the aromatic amino acids, (10) homophenylalanine (Hphe): (11) Tyr; (12) Trp; (13) 2-naphthylalanine (2-Nal); the conformationally-restricted amino acids (14) Pro; (15) 2-aminotetraline-2-carboxylic acid (Atc); the polar amino acids (16) Ser; (17) Thr; (18) Gln; and the charged amino acids (19) Asp; (20) Glu; (21) Arg; (22) Lys; (23) Orn. All 23 new peptides were evaluated for agonistic and, where appropriate, antagonistic activities in in vivo antidiuretic (V2-receptor) and vasopressor (V1a-receptor) assays and in in vitro (no Mg2+) oxytocic assays. The corresponding potencies (units/mg) in these assays for AVP are: 323+/-16; 369+/-6 and 13.9+/-0.5. Peptides 1-9 exhibit the following potencies (units/mg) in these three assays: (1) 379+/-14; 360+/-9; 36.2+/-1.9; (2) 294+/-21: 73.4+/-2.7; 0.33+/-0.02; (3) 249+/-28; 84.6+/-4.3; 4.72+/-0.16; (4) 229+19; 21.4+/-0.6; 2.1+/-0.2; (5) 134+/-5; 31.2+/-0.9; 28.4+/-0.2; (6) 114+/-9; 45.3+2.3; 11.3+/-1.6; (7) 86.7+/-2.5; 4.29+/-0.13; 0.45+/-0.03; (8) 15.5+/-1.5; 0.16+/-0.01; approximately 0.02: (9) 3.76+/-0.03; < 0.02; in vitro oxytocic agonism was not detected. These data show that the aliphatic amino acids Cha, Nle, Leu, Nva and Val are well-tolerated at position 3 in AVP with retention of surprisingly high levels of antidiuretic activity. Peptides 2-9 exhibit significant gains in both antidiuretic/vasopressor (A/P) and antidiuretic/oxytocic (A/O) selectivities relative to AVP. [Thi3]AVP appears to be a more potent antidiuretic and oxytocic agonist than AVP and is equipotent with AVP as a vasopressor agonist. The antidiuretic potencies of peptides 10-23 exhibit drastic losses relative to AVP. They range from a low of 0.018+/-0.001 units/mg for the Lys3 analog (peptide 22) to a high of 24.6+/-4.6 units,mg for the Hphe3 analog (peptide 10). Their vasopressor potencies are also drastically reduced. These range from a low of < 0.002 units/mg for peptide 22 to a high of 8.99+0.44 units/mg for the Atc3 analog (peptide 15). Peptides 10-23 exhibit negligible or undetectable in vitro oxytocic agonism. The findings on peptides 10-23 show that position 3 in AVP is highly intolerant of changes with aromatic, conformationally-restricted, polar and charged amino acids. Furthermore, these findings are in striking contrast to our recent discovery that position 3 in the potent V2/V1a/OT antagonist d(CH2)5D-Tyr(Et)2VAVP tolerates a broad latitude of structural change at position 3 with many of the same amino acids, to give excellent retention of antagonistic potencies. The data on peptides 1-4 offer promising clues to the design of more potent and selective AVP V2 agonists.

Biologically active analogues of arginine vasopressin containing conformationally restricted dipeptide fragments.

In this study we described the synthesis and pharmacological properties of five new analogues of arginine vasopressin (AVP). Four of these analogues contained ethylene-bridged dipeptide Phe-Phe in positions 2 and 3; one had two N-Me-Phe residues. All new peptides were tested for vasopressor and antidiuretic activities. We also estimated the uterotonic activities of these compounds in vitro. Three analogues were highly potent V1-antagonists. One of them, namely [Cpa1,(Phe-Phe)2,3,Val4]AVP, which seemed to not interact with either V2 and oxytocic receptors, was outstandingly selective. It is interesting that the high antipressor potency of our second peptide, [(N-Me-Phe)2,3]AVP, was achieved without modification of position 1. Our results open new possibilities for the design of very potent and selective V1-antagonists of AVP.

Synthesis and Some Pharmacological Properties of Six New Analogs of Arginine-Vasopressin Substituted in Position 2 with β-Thienylalanine or Prolonged on the N-Terminus with 1-Adamantaneacetic Acid

Six new analogs of arginine-vasopressin, four of them substituted in position 2 with β-thienylalanine and two prolonged on the n-terminus by acylation with 1-adamantaneacetic acid, were synthesized on chloromethylated resin using Boc strategy and DCC or DCC-HOBt to form peptide bond. The activity of the analogs was fairly low, however, one of the peptides, namely [Cpp1, Thi2, Val4]AVP, showed selectivity in antiuterotonic, antipressor and anti-antidiuretic effects.

Synthesis of four new V1 antagonists of arginine-vasopressin (AVP) containing new thioacids at position 1 and their vasoconstrictor activity towards isolated mesenteric arterial vessels of rats

In an attempt to determine some of the structural features in position 1 that account for V1 antagonism, four new analogues of arginine-vasopressin were synthesized and the effect of the modifications on the vasoconstrictor activity was checked using isolated mesenteric arterial vessels of rats. The protected precursors required for these analogues were synthesized by a solid phase method of peptide synthesis. One of the reported analogues, namely [1-(4-mercapto-4-tetrahydrothiopyraneacetic acid)., 2-O-methyltyrosine, 8-arginine]vasopressin appears to be a potent competitive antagonist of the vasoconstrictor effect by AVP.

Synthesis and some pharmacologic properties of five novel V 1 or V 1/V 2 antagonists of AVP

Based on [1-(1-mercaptocyclohexaneacetic acid),2-(O-ethyl-D-tyrosine),4-valine]-8-arginine-vasopressin as a model, five new analogues of arginine-vasopressin (AVP) were designed and synthesized. Four of them have in position 1 a large lipophilic substituent, whereas the fifth contains p-chloro-D-phenylalanine at position 2. We found that the anti-antidiuretic potency with 1-mercapto-4-methylcyclohexaneacetic acid is higher than with 1-mercaptocyclohexaneacetic acid (model peptide) in position 1 and this analogue is among the most potent antagonists of the antidiuretic response to AVP known to date. Upon further increase of the size of substituents, antagonistic potency was significantly decreased or totally eliminated. As for the substitution of p-chloro-D-phenylalanine in position 2, we conclude that this modification leads to substantial decrease of the V 2 antagonistic potency.

New analogs of arginine-vasopressin containing β-homo-L-amino acid residues

Four new analogs of arginine vasopressin containing β-homo-L-amino acid residue were synthesized by the solid-phase method. The introduced modifications yielded the following peptides:[β-homo Phe3]AVP (I), [β-homoPro7]AVP (II), [Cpp1, Tyr(Me)2, β-homoPhe3]AVP (III), and[Cpp1,Tyr(Me)2, β-homoPro7]AVP (IV). Agonistic properties of I and II, as well as antagonistic properties of III and IV were decreased, more pronouncedly with analogs substituted in the position 3.