RESUMEN
In order to study the physiological functions of 11-deoxyprostaglandin E1-alpha, a series of its amide derivatives with amino acids and some amines were synthesized using mixed anhydride technique. The myotropic properties of newly synthesized compounds were investigated.
Asunto(s)
Alprostadil/análogos & derivados , Aminas/química , Aminoácidos/química , Prostaglandinas E Sintéticas/síntesis química , Alprostadil/síntesis química , Alprostadil/química , Espectroscopía de Resonancia Magnética , Prostaglandinas E Sintéticas/químicaRESUMEN
Kinin-like properties of two new peptides NRP-11 and P7 which have structural similarity with neurotensin (NT) and kallidin (K) were investigated. It was found that, unlike NT and K, the new peptides possess reduced myotropic and hypotensive activity. On the other hand, similarly to NT and K, the new peptides exhibited a high histamine-releasing activity in rat peritoneal mast cells. Possible central effects are implied for peptide NRP-11 isolated from bovine brain and its fragment P7.
Asunto(s)
Calidina , Cininas , Neuropéptidos , Neurotensina , Secuencia de Aminoácidos , Animales , Bovinos , Cobayas , Liberación de Histamina , Calidina/farmacología , Cininas/farmacología , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Neuropéptidos/farmacología , Neurotensina/farmacología , RatasRESUMEN
Biological properties of a novel vasopressin analogue were investigated. It was found that this analogue has no vasopressor and oxytocic activities but it exhibits a selective antidiuretic effect which is weaker than that of adiuretin (DDAVP). Novel analogue inhibits vasopressor, oxytocic and antidiuretic effects caused by arginine--vasopressin. The usefulness of novel compound as a pharmacological tool--vasopressin antagonist is suggested.
Asunto(s)
Arginina Vasopresina/análogos & derivados , Arginina Vasopresina/antagonistas & inhibidores , Diuréticos/antagonistas & inhibidores , Animales , Arginina Vasopresina/administración & dosificación , Arginina Vasopresina/farmacología , Desamino Arginina Vasopresina/farmacología , Femenino , Masculino , Ratas , Factores de TiempoRESUMEN
Cyclic analogues of substance P of the formula cyclo-[Glu-Phe-Phe-Gly-Leu-Met-NH(CH2)nNH-], where n = 3-10, 12, and open-chain analogues (XVIIIa, b) H-Glu.(NHR)-Phe-Phe-Gly-Leu-Met-NHR, where R = -CH3, -CH2CH2CH3, were synthesized. By NMR spectroscopy it was found that cyclo-compounds with n = 3-8 have regularly arranged structures, stabilized by intramolecular hydrogen bonds. Substances of this type showed less than or equal to 0.1% of the substance P activity on the guinea pig ileum, but some of them antagonize the natural peptide (for compound with n = 5 IC50 = 3.2.10(-6) M). The open-chain compounds proved to have rather high myotropic activity, viz., 22% (R = -CH3) and 8% (R = -CH2CH2CH3) of the substance P activity.
Asunto(s)
Sustancia P/análogos & derivados , Animales , Cobayas , Íleon/efectos de los fármacos , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/farmacología , Conformación Proteica , Sustancia P/antagonistas & inhibidoresRESUMEN
1 alpha-beta-carboxypropionyl-cyclo(9----1 epsilon)-[Lys1, Gly6]bradykinin (Suc-c[Lys1, Gly6]B), 1 alpha-beta-carboxypropionyl-cyclo(10----1 epsilon)kallidin (Suc-cK), cyclo(10 gamma----1 epsilon)-[Glu10]kallidin (c[Glu10]K) and cyclo(11 gamma----1 epsilon)kallidylglutamic acid (cKG) were synthesized. Suc-c[Lys1, Gly6]B and Suc-cK were prepared by acylating the appropriate cyclopeptides with succinic anhydride. c[Glu10]K and cKG were obtained by the classic peptide synthesis, the cyclization being carried out with 61 and 42% yields, respectively. The protecting groups were then eliminated by catalytic hydrogenation. c[Glu10]K and cKG exerted myotropic action on isolated rat uterus (alpha 0.73 and 0.89, pD2 6.61 and 8.61, respectively). cKG displayed direct myotropic activity with respect to electrically stimulated rat vas deferens and guinea-pig ileum, potentiating the contractions (by 100%) in response to electric stimuli. c[Glu10]K and cKG elicit histamine release in isolated rat mast cells (EC30 4.91.10(-5) and 1.47.10(-6) M, respectively). Both cyclopeptides alter arterial pressure following intravenous administration to anaesthetized rats, cats and dogs and affect heart rate. In all assays cKG is more active than c[Glu10]K. Suc-c[Lys1, Gly6]B and Suc-cK do not possess myotropic, histamine-releasing or hypotensive activity, though they were found to elicit a transient increase of bloodflow in cats and dogs.
Asunto(s)
Bradiquinina/análogos & derivados , Secuencia de Aminoácidos , Animales , Presión Sanguínea/efectos de los fármacos , Bradiquinina/genética , Bradiquinina/farmacología , Gatos , Perros , Femenino , Cobayas , Liberación de Histamina/efectos de los fármacos , Datos de Secuencia Molecular , Contracción Muscular/efectos de los fármacos , Miometrio/efectos de los fármacos , RatasRESUMEN
Five angiotensin cycloanalogues have been synthesised by classical methods of peptide chemistry, cyclisation being carried out via pentafluorophenyl esters. Cycloanalogues (I-IV) with a fixed potential turn in the C-terminal part of the angiotensin molecule inferred on the basis of physico-chemical data do not possess angiotensin-like activity. Compounds (V) with enlarged cycle shows decreased pressor effects as compared with angiotensin. By means of circular dichroism chiroptical properties of the compounds in water and ethanol were examined.
Asunto(s)
Angiotensina II/análogos & derivados , Péptidos Cíclicos/síntesis química , Secuencia de Aminoácidos , Angiotensina II/análisis , Angiotensina II/síntesis química , Angiotensina II/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Fenómenos Químicos , Química , Dicroismo Circular , Técnicas In Vitro , Datos de Secuencia Molecular , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Péptidos Cíclicos/análisis , Péptidos Cíclicos/farmacología , RatasRESUMEN
Two solution syntheses of cyclo(11----5 epsilon)-[Lys5]substance P-(5-11) (CLP) were carried out. The first synthesis involved the stepwise elongation of the peptide chain starting from glycine tert-butyl ester. At the stage of hexapeptide deprotection, the cleavage of Boc and But groups was accompanied by tert-butylation of the Met residue. Cyclization was carried out via a pentafluorophenyl ester intermediate. The benzyloxycarbonyl-cyclopeptide (Z-CLP) formed was deprotected by catalytic transfer hydrogenation. A (3 + 4) block coupling strategy was used in course of the repeated preparation of the linear precursor of CLP. Optimization of the cyclization and subsequent deprotecting stages lead to increased yields and facilitated the synthetic procedure. Z-CLP was found to possess myotropic activity on isolated guinea pig ileum (alpha = 0.55 +/- 0.18; pD2 = 7.97 +/- 0.20), whereas CLP was inactive in these experiments. Z-CLP causes a slight two-phase effect on arterial pressure in rats, CLP being inactive. Similar to substance P, CLP displays an antidepressant-like effect in mice as indicated by the swimming test.
Asunto(s)
Fragmentos de Péptidos/síntesis química , Péptidos Cíclicos/síntesis química , Sustancia P/análogos & derivados , Animales , Presión Sanguínea/efectos de los fármacos , Fenómenos Químicos , Química , Cobayas , Técnicas In Vitro , Actividad Motora/efectos de los fármacos , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Péptidos Cíclicos/farmacología , Ratas , Sustancia P/síntesis química , Sustancia P/farmacologíaRESUMEN
Biological properties of five novel angiotensin analogues synthesized, using the conventional methods of peptide chemistry, have been studied. Cyclization was attained by means of amide linkage with the aid of diphenylphosphorylazide or pentafluorophenyl esters. Unlike the natural hormone, the cyclic analogues of angiotensin show no pressor activity, but elicit a depressor effect untypical of angiotensin. A slight pressor activity was exhibited by the compound containing aspartic acid in position 1. The cyclic analogues in question release histamine from peritoneal mast cells in rats.
Asunto(s)
Angiotensina II/análogos & derivados , Péptidos Cíclicos/síntesis química , Aldosterona/biosíntesis , Angiotensina II/síntesis química , Angiotensina II/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Fenómenos Químicos , Química , Relación Dosis-Respuesta a Droga , Femenino , Liberación de Histamina/efectos de los fármacos , Técnicas In Vitro , Masculino , Péptidos Cíclicos/farmacología , RatasRESUMEN
New cyclic analogues of neurotensin (NT): [cyclo (13----8), Gly8]NT-(8-13), [cyclo (13----7), Gly7]NT-(7-13), [cyclo (13----5 epsilon), Lys5]NT-(5-13), [cyclo (13----4 epsilon), Lys4]NT-(4-13), and their linear precursors have been synthesized. The latter (protected linear compounds) were prepared by solid-phase peptide synthesis, and cyclization was attained by using diphenylphosphoryl azide. Cyclization of C-terminal hexa- and octapeptide fragments of NT was found to lead to cycloanalogues possessing high depressor activity. As judged by CD spectral data in aqueous solution, the cyclohexapeptide analogue has a relatively rigid conformation different from its linear counter-part and the NT-(9-13) fragment, whereas NT, its cyclohepta- and cyclononapeptides have random structure.
Asunto(s)
Neurotensina/análogos & derivados , Péptidos Cíclicos/síntesis química , Secuencia de Aminoácidos , Animales , Presión Sanguínea/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Dicroismo Circular , Cobayas , Íleon/efectos de los fármacos , Técnicas In Vitro , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Neurotensina/síntesis química , Neurotensina/farmacología , Péptidos Cíclicos/farmacología , Conformación Proteica , RatasRESUMEN
Cyclic analogs of bradykinin (CBK) and kallidin (CK) have a weak myotropic activity and a marked and prolonged hypotensive effect unlike linear bradykinin (BK) and kallidin (K) which produce a short-term hypotension and considerable contraction of rat uterus smooth muscles. Myotropic effects of BK and CK were significantly inhibited by phentolamine, methysergide, papaverine and verapamil. Atropine, diphenhydramine and propranolol have no influence on the kinin-induced myotropic responses. The prolonged decrease in blood pressure induced by CBK and CK is observed in un- and anesthetized normotensive, spontaneously hypertensive rats and rats with renovascular hypertension and is absent from anesthetized cats and guinea-pigs. This indicates the species specificity of cyclokinins. Indomethacin, diphenhydramine and methysergide failed to influence the BK- and CK-induced hypotensive effects on anesthetized rats. CaCl2 did not influence the magnitude of the hypotensive effect of BK and CK, however, it significantly shortened the duration of the CK-induced hypotensive effect. In vitro CBK and CK inhibited activity of kininase II in a similar manner (at a concentration range of 10(-5) M) but to a less extent than BK (10(-7)-10(-6) M). It is suggested that the hypotensive effect of CK is mediated at least partly via Ca2+-dependent systems and inhibition of kininase II.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Bradiquinina/análogos & derivados , Bradiquinina/farmacología , Calidina/análogos & derivados , Contracción Uterina/efectos de los fármacos , Animales , Calcio/fisiología , Gatos , Depresión Química , Femenino , Cobayas , Humanos , Calidina/farmacología , Masculino , Peptidil-Dipeptidasa A/sangre , Ratas , Especificidad de la EspecieRESUMEN
The comparative effects of thyroliberin (TRH), pentagastrin, C-terminal tripeptides of gastrin (MNF), luliberin (RPG) and its analog (RPF), oxytocin (PLG) and N-terminal tripeptide of angiotensin (NRV) on the glucose concentration in mouse blood, as well as the interrelationship between the peptides under study and insulin and somatostatin, were studied. It was found that all the peptides (except PLG) at doses 5, 50 and 100 mg/kg (intraperitoneally) exert a hypoglycemic effect comparable to that of insulin at the dose of 0,15 MU/kg (subcutaneously). The dose-dependent effect is observed only in the case of TRH. Somatostatin reverses the hypoglycemic action of TRH, MNF and NRV. TRH and RPF decrease the glucose-induced rise in insulin concentration measured by RIA. The structure-activity relationship and possibility of the formation of endogenous peptide hormone fragments as products of hormone molecules enzymatic cleavage and their glucoregulatory role are discussed.
Asunto(s)
Glucemia/metabolismo , Homeostasis/efectos de los fármacos , Hormona Liberadora de Tirotropina/farmacología , Angiotensinas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Hormona Liberadora de Gonadotropina/farmacología , Ratones , Pentagastrina/farmacología , Fragmentos de Péptidos/farmacología , Relación Estructura-ActividadRESUMEN
The authors studied comparatively the properties of two angiotensin II analogues, a new compound (1-hydantoin acid, 5-valine, 8-alanine)-angiotensin II (compound III) and (1-asparagine, 5-valine, 8-alanine)-angiotensin II (compound II), as of the myotropic action of angiotensinamide (these experiments were conducted on the rat isolated ascending colon); pressor action of the hormone was investigated in experiments on anesthetized rats. A competitive character of the antagonism--within the range of low concentrations of the analogues--10(-10)--10(-9) M/l--was revealed in vitro. No antagonism was expressed against the nonspecific myotropic agents--acetylcholine and bradykinin. In vivo compounds II and II manifested the antagonistic action against angiotensinamide beginning from the doses of 100 and 50 gamma/kg, respectively.