RESUMEN
Continuing our efforts to obtain potent and selective analogues of AVP we synthesized and pharmacologically evaluated ten new compounds modified at position 2 with alpha-2-indanylglycine or its D-enantiomer (Igl or D-Igl, respectively). All the peptides were tested for pressor, antidiuretic, and in vitro uterotonic activities. We also determined the binding affinity of these compounds to human OT receptor. The Igl(2) substitution resulted in a significant change of the pharmacological profile of the peptides. The new analogues were moderate or potent OT antagonists (pA(2) values ranging from 7.19 to 7.98) and practically did not interact with V(1a) and V(2) receptors. It is worth emphasizing that these new peptides were exceptionally selective. On the other hand, the D-Igl(2) substituted counterparts turned out to be weak antagonists of the pressor response to AVP and displayed no antidiuretic activity. Some of the results were unexpected, e.g. dual activity in the rat uterotonic test in vitro: the D-Igl peptides showed a strong antioxytocic potency (pA(2) values ranging from 7.70 to 8.20) at low concentrations and full agonism at high concentrations. The results provided useful information about the SAR of AVP analogues.
Asunto(s)
Arginina Vasopresina/química , Glicina/análogos & derivados , Indanos/química , Animales , Arginina Vasopresina/análogos & derivados , Cromatografía Líquida de Alta Presión , Cromatografía en Capa Delgada , Femenino , Glicina/química , Técnicas In Vitro , Ratas , Ratas Wistar , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , EstereoisomerismoRESUMEN
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.
Asunto(s)
Fármacos Antidiuréticos/síntesis química , Arginina Vasopresina/análogos & derivados , Arginina Vasopresina/síntesis química , Ácidos Carboxílicos/síntesis química , Receptores de Vasopresinas/agonistas , Animales , Fármacos Antidiuréticos/farmacología , Antagonistas de los Receptores de Hormonas Antidiuréticas , Arginina Vasopresina/farmacología , Presión Sanguínea/efectos de los fármacos , Ácidos Carboxílicos/farmacología , Femenino , Técnicas In Vitro , Conformación Proteica , Ratas , Ratas Wistar , Relación Estructura-Actividad , Contracción Uterina/efectos de los fármacosRESUMEN
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.
Asunto(s)
Aminoácidos Cíclicos/química , Arginina Vasopresina/análogos & derivados , Arginina Vasopresina/química , Arginina Vasopresina/farmacología , Ácido 3-Mercaptopropiónico/química , Ácido 4-Aminobenzoico/química , Secuencia de Aminoácidos , Animales , Arginina Vasopresina/síntesis química , Ácidos Ciclohexanocarboxílicos/química , Diuréticos/farmacología , Femenino , Masculino , Modelos Biológicos , Datos de Secuencia Molecular , Conformación Proteica , Ratas , Ratas Wistar , Relación Estructura-Actividad , Vejiga Urinaria/efectos de los fármacos , Útero/efectos de los fármacos , Vasoconstrictores/farmacologíaRESUMEN
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).
Asunto(s)
Arginina Vasopresina/análogos & derivados , Arginina Vasopresina/química , Oligopéptidos/química , Secuencia de Aminoácidos , Animales , Arginina Vasopresina/farmacología , Presión Sanguínea/efectos de los fármacos , Estrógenos/fisiología , Femenino , Masculino , Oligopéptidos/síntesis química , Conformación Proteica , Ratas , Ratas Wistar , Útero/efectos de los fármacos , Útero/fisiología , Vasopresinas/farmacologíaRESUMEN
It is generally accepted that the conformation of the N-terminal part of neurohypophyseal hormones analogues is important for their pharmacological activity. In this work, we decided to investigate how the substitution of positions 2 and 3 with the ethylene-bridged dipeptide would alter the pharmacological properties of OT, [Mpa1]OT, and [Cpa1]OT (OT=oxytocin; Mpa=3-mercaptopropionic acid; Cpa=1-mercaptocyclohexaneacetic acid) and to investigate how a bulky 3,3-diphenyl-L-alanine residue incorporated in position 2 of AVP, [Mpa1]AVP, and [Cpa1]AVP (AVP=arginine vasopressin) would change the pharmacological profile of the compounds. The next analogues, [Val4]AVP, [Mpa1,Val4]AVP, and [Cpa1,Val4]AVP, had N-benzyl-L-alanine introduced at position 3. The last peptide was designed by Cys1 substitution in AVP by its sterically restricted bulky counterpart, alpha-hydroxymethylcysteine. All the peptides were tested for their in vitro uterotonic, pressor, and antidiuretic activities in the rat. The results of these assays showed that the reduction of conformational freedom of the N-terminal part of the molecule had a significant impact on pharmacological activities.
Asunto(s)
Arginina Vasopresina/análogos & derivados , Arginina Vasopresina/síntesis química , Dipéptidos/síntesis química , Oxitocina/análogos & derivados , Oxitocina/síntesis química , Ácido 3-Mercaptopropiónico/química , Animales , Fármacos Antidiuréticos/síntesis química , Fármacos Antidiuréticos/farmacología , Arginina Vasopresina/farmacología , Dipéptidos/farmacología , Femenino , Masculino , Conformación Molecular , Oxitocina/farmacología , Ratas , Ratas Wistar , Relación Estructura-Actividad , Contracción Uterina/efectos de los fármacos , Vasoconstrictores/síntesis química , Vasoconstrictores/farmacologíaRESUMEN
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.
Asunto(s)
Aminoácidos Cíclicos/química , Aminoácidos Cíclicos/farmacología , Arginina Vasopresina/química , Animales , Diuresis/efectos de los fármacos , Femenino , Ratas , Ratas Wistar , Útero/efectos de los fármacosRESUMEN
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-Nal2,Val4]AVP, which appears practically not to interact with V1a and V2 receptors, is exceptionally selective. Our results open new possibilities for the design of very potent and selective oxytocin antagonists in vitro.
Asunto(s)
Arginina Vasopresina/análogos & derivados , Vasoconstrictores/administración & dosificación , Vasoconstrictores/síntesis química , Animales , Arginina Vasopresina/síntesis química , Arginina Vasopresina/farmacología , Diuresis/efectos de los fármacos , Electrólitos/orina , Isomerismo , Masculino , Oxitocina/antagonistas & inhibidores , Ratas , Ratas Wistar , Vasoconstrictores/farmacologíaRESUMEN
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.
Asunto(s)
Arginina Vasopresina/análogos & derivados , Secuencia de Aminoácidos , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas , Arginina Vasopresina/síntesis química , Arginina Vasopresina/farmacología , Dipéptidos/síntesis química , Dipéptidos/farmacología , Diuréticos/antagonistas & inhibidores , Electrólitos/orina , Masculino , Conformación Proteica , Ratas , Ratas Wistar , Relación Estructura-Actividad , Vasoconstrictores/farmacologíaRESUMEN
The synthesis and some pharmacological properties of two sets of analogues, one consisting of six peptides with 1-aminocyclohexane-1-carboxylic acid (Acc) in position 2 and the other with the amino acid in position 3, have been described. All the peptides were tested for their pressor, antidiuretic, and uterotonic in vitro activities. The Acc(2) modification has been shown to selectively modulate the activities of the analogues. Four of the compounds were highly potent antidiuretic agonists with different pressor and uterotonic activities. On the other hand, the 3-substituted counterparts failed to exhibit any of the activities. One exception was provided by the [Mpa(1),Acc(3),Val(4),D-Arg(8)]VP analogue, which exhibited antidiuretic activity matching that of AVP, yet, unlike AVP, it was fairly selective.