Single diastereomeric desaminotyrosylalanyl tetra- and heptapeptides with opioid antagonistic activity

The N-terminal dipeptide Tyr-d -Ala of a p-selective agonist, dermorphin tetrapeptide (DT, H-Tyr-d -Ala-Phe-Gly-NH₂) and δ-selective agonist deltorphin C (DEL-C, H-Tyr-d -Ala-Phe-Asp-Val-Val-Gly-NH₂) was changed into an aminodiacyl moiety. The relevant synthetic step is a nucleophilic substitution of bromine from a chiral 2-bromopropanamide by the amino group of tyrosine, with overall retention of configuration. The resulting pseudo tetra- and heptapeptides I-VI were characterized for μ and δ-opioid receptor binding properties using [³H]DAGO and [³H]DPDPE, respectively, and in a bioassay using guinea pig ileum (GPI) and mouse vas deferens (MVD). As a result of chemical alteration of N-terminal dipeptide moiety, all synthesized analogs showed considerable reduction in opioid receptor affinity compared to μ and δ-prototypes (500-fold on the μ-site, analog I , and 125-fold on the δ-site, analog IV ). Interestingly, analogs I and IV showed moderate antagonist activity, respectively, on GPI and MVD, with pA₂ values of 6.05 and 6.82. Analog IV did not exhibit the δ-antagonist potency and δ-selectivity of TIPP peptides. © Munksgaard 1995.