CONFORMATIONALLY CONSTRAINED DELTORPHIN ANALOGS WITH 2-AMINOTETRALIN-2-CARBOXYLIC ACID IN POSITION-3

Two approaches to the design of very active and highly selective delta opioid peptides were used to obtain new deltorphin analogs with alter ed hydrophobic and stereoelectronic properties. Deltorphin I and II an alogs were synthesized involving the substitution of Ile instead of Va l at positions 5 and 6 in the address domain and 2-aminotetralin-2-car boxylic acid (Ate) instead of Phe in the message domain. The peptides were agonists in the subnanomolar range in the MVD assay and in the mi cromolar or higher range in the GPI assay, showing a very high selecti vity for delta receptors. A very similar trend could be observed in ra dioreceptor binding assays in which selective tritiated opioid ligands were used. (R)- and (S)-Atc-deltorphins exhibited similar K-i values in the binding assay, with almost complete loss of the stereospecifici ty of the binding. Conformational studies provided evidence for little disturbance of the backbone conformational equilibrium when Phe(3) is replaced by (S)- or (R)-Atc. The use of the Atc constraint gives addi tional evidence that, during its interaction with the delta receptor, the side chain of residue 3 adopts the trans conformation at chi(1).