RESUMEN
A cyclic analog of enkephalin, cyclo(Lys-Tyr-DMet-Gly-Phe-Pro-) and two corresponding linear hexapeptides with lysine residue on the N- and C-termini of the pentapeptide sequence, Lys-Tyr-DMet-Gly-Phe-Pro and Tyr-DMet-Gly-Phe-Pro-Lys were synthesized by classical and solid phase methods of peptide chemistry. The cyclic analog exhibited significantly prolonged analgesic effect, evaluated by the "tail pinch" method after intracysternal injection to mice. The cycloanalog also had a weak influence on the peripheral opiate receptors of the isolated segment of guinea pig iliac intestine. Addition of the lysine residue to the N-terminus of the pentapeptide sequence enhanced by an order of magnitude the selectivity of binding of the analog with opiate receptors of mu-type.
Asunto(s)
Analgésicos/síntesis química , Encefalinas/síntesis química , Péptidos Cíclicos/síntesis química , Secuencia de Aminoácidos , Analgésicos/farmacología , Animales , Dicroismo Circular , Preparaciones de Acción Retardada , Encefalinas/farmacología , Cobayas , Íleon/efectos de los fármacos , Íleon/metabolismo , Técnicas In Vitro , Ratones , Datos de Secuencia Molecular , Péptidos Cíclicos/farmacología , Receptores Opioides/efectos de los fármacosRESUMEN
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
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
The spatial structure of an enkephaline cycloanalogue Lys-Tyr-Gly-Gly-Phe-Leu--has been investigated by means of energy calculations, fluorescence and CD-spectroscopy. Despite the high conformational mobility of the cycloanalogue, little resemblance exists between its and parent peptide's low-energy structures. Conformational factors for possible mechanisms of interaction between specific enkephalin receptors and cycloanalogue are discussed.
Asunto(s)
Encefalina Leucina/análogos & derivados , Péptidos Cíclicos , Dicroismo Circular , Conformación ProteicaRESUMEN
Using solid-phase approach, new cyclic and linear analogues of C-terminal neurotensin (NT) fragments were synthesized and their vasodepressor and miotropic activities were assayed. The cyclic structures were fixed by a peptide bond linking the lysine epsilon-amino group with the C-terminal carboxyl. Cyclization was performed by using pentafluorophenyl esters or diphenylphosphorylazide. [Phe5]-cyclo(13----6 epsilon)NT-(5-13) was found to possess high depressor activity showing certain selectivity with respect to smooth vasal muscles. Circular dichroism spectra of aqueous solutions of linear and cyclic penta- and octapeptide analogues of neurotensin indicate that the linear pentapeptide in solution adopts a folded structure, while the neurotensin fragment NT-(6-13) has an unordered structure. Cyclization of the latter fragment leads to dramatic restriction of its conformational mobility resulting in a relatively rigid structure.
Asunto(s)
Neurotensina/análogos & derivados , Fragmentos de Péptidos/síntesis química , Secuencia de Aminoácidos , Animales , Presión Sanguínea/efectos de los fármacos , Fenómenos Químicos , Química , Dicroismo Circular , Cobayas , Íleon/efectos de los fármacos , Técnicas In Vitro , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Neurotensina/síntesis química , Neurotensina/farmacología , Fragmentos de Péptidos/farmacología , Conformación Proteica , Ratas , Relación Estructura-ActividadRESUMEN
To assess the role of amino acid sequence ACTH 19-24 in the corticotropin structure and steroidogenic activity, the analogues of ACTH-(11-24)-tetradeca- and ACTH-(1-24)-tetracosapeptides containing hexaglycine, hexaphenylalanine, hexaglutamic acid or hexalysine instead of the natural 19-24 sequence have been synthesized by conventional methods. All these compounds in water have the CD curves characteristic of random coil, CD spectra of analogue ACTH-(1-24)-tetracosapeptide and hexalysine-containing analogue ACTH-(11-24)-tetradecapeptide in trifluoroethanol indicate the presence of alpha-helices. The latter compound manifested higher steroidogenic activity than ACTH-(11-24)-tetradecapeptide. All the other analogues were either less active than ACTH-(1-24)-tetracosapeptide or inactive over the concentration range 10(-5)-10(2) mg/ml, thereby testifying to functional importance of the 19-24 sequence for manifesting full steroidogenic activity.