Hidekazu Ouchi

Dermorphin and deltorphin heptapeptide analogues: replacement of Phe residue by Dmp greatly improves opioid receptor affinity and selectivity.

The usefulness of 2,6-dimethylphenylalanine (Dmp) as a Phe surrogate in two opioid peptides, dermorphin (DM) and deltorphin II (DT), was investigated. Compared to DM, [L-Dmp(3)]DM (1) showed a 170-fold increase in mu affinity and only a 4-fold increase in delta affinity, resulting in a 40-fold improvement in mu receptor selectivity. Compared to DT, [L-Dmp(3)]DT (3) showed a 22-fold increase in delta affinity and somewhat of a loss in mu affinity, and consequently a marked (75-fold) improvement in delta receptor selectivity. The D-Dmp replacement, however, resulted in a great loss in receptor selectivity in each of the peptides. The specific receptor interactions of 1 and 3 were confirmed by in vitro bioassays. Analogues 1 and 3 seem to be useful as pharmacological tools for the study of opioid systems.

Regioselective aromatic substitution of 6,8-dihydroxy-4-ethoxycarbonyl-2H-isoquinolin-1-one derivatives using the stille coupling reaction

The novel synthesis of 6- or 7-aromatic substituted 2H-isoquinolin-1-ones, by two different routes is described. In the first route, 7-substituted derivatives were prepared by regioselective iodination at the 7-position of 6,8-dihydroxy-4-ethoxycarbonyl-2H-isoquinolin-1-one derivatives (1) followed by the Stille coupling reaction. In the second route, 6-subsutituted derivatives were prepared by the selective triflation of the 6-hydroxy group of 1 followed by the Stille coupling reaction.