RESUMEN
Three new analogues of vasopressin, viz. des-Gly9-[Phe2, Orn8]vasopressin, diglycyl-des-Gly9-[Phe2, Orn8]vasopressin, and diglycyl-des-Gly9-[Val4, Orn8]vasopressin, were synthesized to investigate the structure-function relationship. Hormonal (vasopressor, antidiuretic, uterotonic, galactogogic) activities of the new compounds were determined, their effect on elaboration and retention of the active avoidance behaviour in rats was studied.
Asunto(s)
Vasopresinas/síntesis química , Animales , Reacción de Prevención/efectos de los fármacos , Fenómenos Químicos , Química , Dicroismo Circular , Condicionamiento Clásico/efectos de los fármacos , Memoria/efectos de los fármacos , Ornipresina/análogos & derivados , Ornipresina/síntesis química , Ornipresina/farmacología , Conejos , Ratas , Vasopresinas/farmacologíaRESUMEN
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
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.