Enkephalin analogs containing amino sulfonic acid and amino phosphonic acid residues at position 5

Abstract

Enkephalins, the endogenous opioid peptides: Tyr-Gly-Gly-Phe-Met and -Leu [ 11, have been known to show much higher agonist potency in the mouse vas deferens preparation (MVD) than in the guinea-pig ileum assay system (GPI) [2-61. The high MVD/GPI potency ratio is characteristic of enkephalins and of their synthetic analogs unless the pentapeptides are terminated by an amide function. For instance, potency ratios calculated for Met-enkephalin, its D-Ala2 analog and [D-Ala2, Met’]-enkeph~~ide were 9.0,8.4 and 2.0, respectively [2]. The MVDlGPI ratio for &endorphin, the 3 l-residue opioid peptide of the pituitary, is -1.2 and for nonpeptide narcotics, e.g., normorphine and morphine even smaller [2,4-61. Accordingly, the acidic COOH group at the C-terminus is essential for the ‘enkephalinoid’ character of pentapeptides. Starting from this consideration we synthesized some analogs of norleucine (Nle)-enkephahn in which the terminal COOH group is replaced by SOaH and POsH, group, respectively, i.e., Me’ is ~bstituted by a-amino~nt~e-s~fonic acid (NleS) and ff-amino-pentanephosphonic acid (MeP), respectively. The dissociation constant of a sulfonic acid or a phosphonic acid is known to be higher than that of the corresponding carboxylic acid. For instance, pKL values of taurine and p&nine are 1.5 and 3.6, respectively [7]. Similarly, pKH of glycine is 2.34 while the two pKH values of amino-methane-phosphonic acid are 1.85 and 5.35, respectively [S]. The more acidic terminal groups were expected to improve the enkephalin-like activity of the peptides. To study this question the opiate agonist potencies of the new compounds were