Enkephalin analogs. Introduction of stereochemical constraints, metal binding sites and fluorescent groups

Abstract

There has been considerable speculation on the biologically active conformations of the enkephalins and their possible structural similarity to the opiates [1- 4]. A number of models have been proposed on the basis of theoretical calculations [2] and computer modelling [3]. Recent NMR studies suggest a high degree of conformational flexibility at Gly² and Gly³ implying that a favoured conformation does not exist in aqueous solution [5]. The replacement of the Gly residues by Aib residues will greatly restrict the available conformations at positions 2 and 3 of the pentapeptides and may thereby allow a better definition of the steric requirements for biological activity. This approach appears particularly attractive in view of the extremely well defined conformations adopted by Aib containing peptides [6 -10]. An earlier report described the synthesis of Aib² - Met³ -enkephalin-amide [11]. Here we present the preparation and compare the biological properties of the Aib², Aib³, and Aib² - Aib³ Met⁵ -enkephalin derivatives. The properties of 3-nitro-Tyr analogs, designed to bind paramagnetic NMR shift probes and a fluorescent Aib² analog developed for studies of receptor interactions, are also described.