RESUMEN
[1-(beta,beta-Pentamethylene-beta-mercaptopropionic acid),2-(O-ethyl)-D- tyrosine,4-valine,9-desglycine]arginine-vasopressin (SK&F 101926, 1), a potent in vivo and in vitro vasopressin V2 receptor antagonist, was recently tested in human volunteers and shown to be a full antidiuretic agonist. A new animal model for vasopressin activity has been developed in dogs that duplicates the clinical agonist findings exhibited with SK&F 101926. In this model we have discovered that substitution of a cis-4'-methyl group on the Pmp moiety at residue 1 of vasopressin antagonists results in substantially reduced agonist activity compared to the unsubstituted molecule (SK&F 101926). The corresponding analogue with a trans-4'-methyl group exhibits more agonist activity than the cis molecule. These findings can be explained by viewing the biological activities of compounds such as 1 as the interaction of the vasopressin receptor with a number of discrete molecular entities, conformers of 1, which present different pharmacophores. Models have been developed to assist in the understanding of these results.
Asunto(s)
Arginina Vasopresina/análogos & derivados , Vasopresinas/antagonistas & inhibidores , Inhibidores de Adenilato Ciclasa , Secuencia de Aminoácidos , Animales , Arginina Vasopresina/síntesis química , Arginina Vasopresina/metabolismo , Arginina Vasopresina/farmacología , Unión Competitiva , Bioensayo , Sangre , Fenómenos Químicos , Química , Perros , Humanos , Médula Renal/enzimología , Conformación Molecular , Concentración Osmolar , Ratas , Receptores de Angiotensina/efectos de los fármacos , Receptores de Angiotensina/metabolismo , Receptores de Vasopresinas , Estereoisomerismo , Relación Estructura-Actividad , Porcinos , OrinaRESUMEN
We report the synthesis and biological activity of a series of analogues of the vasopressin antagonists [Pmp1,D-Tyr(Et)2,Val4]arginine-vasopressin (1) and [Pmp1,D-Tyr(Et)2,Val4,desGly9]arginine-vasopressin (2), where part or all of the tripeptide tail has been replaced by a simple alkyldiamine [NH(CH2)nNH2] or (aminoalkyl)guanidine [NH(CH2)nNHC(= NH)NH2] in order to examine the effects that variation of the length and orientation of the tripeptide tail have on renal vasopressin (V2) receptor antagonist activity. The results show that the entire tripeptide tail (Pro-Arg-Gly-NH2) can be replaced by an alkyldiamine or an (aminoalkyl)guanidine, compounds 15 and 16, respectively, indicating that there is no orientational requirement for the basic functional group coming off the cyclic hexapeptide ring. Also, there seems to be an "optimal" distance between the basic functional group and the hexapeptide ring since receptor affinity of the antagonists begins to fall off when the basic functional group is too close (compound 13) or extends too far (compounds 8-10) from the hexapeptide ring. These results suggest all that is necessary for retention of antagonist affinity and potency is a basic functional group, amine or guanidine, extended an optimal distance from the hexapeptide ring.
Asunto(s)
Vasopresinas/antagonistas & inhibidores , Animales , Humanos , Masculino , Conformación Molecular , Péptidos/síntesis química , Péptidos/farmacología , Ratas , Receptores de Angiotensina/efectos de los fármacos , Receptores de Vasopresinas , Relación Estructura-Actividad , PorcinosAsunto(s)
Vasopresinas/síntesis química , Adenilil Ciclasas/metabolismo , Animales , Membrana Celular/metabolismo , Médula Renal/metabolismo , Receptores de Angiotensina/metabolismo , Receptores de Vasopresinas , Relación Estructura-Actividad , Porcinos , Vasopresinas/antagonistas & inhibidores , Vasopresinas/farmacologíaAsunto(s)
Eritema/genética , Extremidades/fisiopatología , Carbohidratos/efectos adversos , Niño , Preescolar , Pie Equinovaro , Caries Dental/inducido químicamente , Femenino , Humanos , Masculino , Periodontitis/etiología , Tetraciclina/uso terapéutico , Decoloración de Dientes/inducido químicamenteAsunto(s)
Dermatitis por Contacto/etiología , Bases Oleosas/efectos adversos , Perfumes , Excipientes Farmacéuticos/efectos adversos , Gramicidina/farmacología , Humanos , Masculino , Persona de Mediana Edad , Neomicina/farmacología , Nistatina/farmacología , Pruebas Cutáneas , Triamcinolona Acetonida/farmacologíaRESUMEN
Purified HIV-1 protease hydrolyzes H-Ser-Gln-Asn-Leu-Phe(NO2)-Leu-Asp-Gly-NH2 (Peptide 1) and acetyl-Arg-Lys-Ile-Leu-Phe(NO2)-Leu-Asp-Gly-NH2 (Peptide 2) between the (p-nitro)phenylalanyl and leucyl residues. The cleavage of Peptides 1 and 2 resulted in a decrease in uv absorbance at 310 nm. The HIV-1 protease-catalyzed peptidolysis of Peptides 1 and 2 was characterized by a linear time course at substrate turnover of less than 20%. The solubilities of these substrates at pH 5.0 were sufficient to provide initial rate measurements over a concentration range of 0.05-0.5 mM. Steady-state kinetic data and inhibition constants using both spectrophotometric and high performance liquid chromatography (HPLC) analysis of the peptidolysis of these substrates resulted in comparable values.