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 ...