Synthesis and Conformational Analysis of Some Leu- and Met-Enkephalin Analogues

Synthesis and Conformational Analysis of Some Leu- and Met-Enkephalin Analogues Abstract The intriguing relationship between morphine and the endogenous opioid peptide leucine enkephalin and methionine enkephalin, discovered in 1975 by Hughes and Kosterlitz [1] has stimulated numerous efforts to delineate the structural basis for their common analgesic effects.[2] Of the pharmacological viewpoint, endogenous enkephalins are very similar to morphine: they also have analgesic properties, lead to physical addiction and depression of respiration, depress the cough reflex, stimulate the release of vasopressin, and inhibit gastric fluid secretion and the motor activity of the intestine. In addition, they appear to act as tumor suppressant and as inhibitors of cell division .[3] The inherent mobility of the enkephalin framework, its rapid degradation in vivo, [4] and the presence of multiple receptors has hampered assessment of its bioactive conformations. Several turn conformations have been proposed based upon computational models, X-ray crystallography, and spectroscopic studies. In order to examine these hypotheses and explore the role of potential bioactive turn conformations of enkephalin, we have designed, synthesized and evaluated several linear and cyclic modified encephalin. Here we report the design and synthesis of the peptide mimetic of Leu- and Met-enkephalin deriving from the substitutions of Leu5 and Met5 with Ile, Nle, Val and Nva. Furthermore we synthesized all homologues having one or two amino acid with D configuration. Based upon computational models and X-ray crystallography [5] of this compounds we studied the possibility to obtain only the biologically active conformation of the single peptide, introducing (a) a partial conformational restriction with a rigid part of main chain and (b) a total conformational restriction with end to end cyclization of peptide main chain. References [1] Huges, J.; Smith, T.W.; Kosterlitz, H.W.; Fothergill, L.A.; Morgan, B.A.; Nature 1975 258, 577. [2] Schiller, P.W.; in The Peptides: Analysis, Synthesis, Biology; Udenfried, S.; Meienhofer, J.; Eds.; Academic Press, Orlando, FL, 1990; Vol.6 pp. 219-268. [3] Maneckjee, R.; Minna, J.D.; Proc. Natl. Acad. Sci. USA 1992 89, 1169. [4] Roques, B.P.; Garbay-Jaureguiberry, C.; Oberlin, R.; Anteunis, M.; Lala, A.K.; Nature 1976 262, 778. [5] Fenude, E.; Casalone, G.; Acta Cryst. Section C 1996 52, 973-978.