SYNTHESIS AND OPIOID BINDING-ACTIVITY OF DERMORPHIN ANALOGS CONTAINING CYCLIC BETA-AMINO ACIDS

In the present work, eight conformationally constrained analogues of t he mu specific opioid peptide dermorphin were synthesized by replacing D-Ala(2) with stereoisomers of beta-amino-cycloalkane or cycloalkene carboxylic acids. The resulting peptides were tested for their potency to mu and delta opioid binding sites of rat brain membranes labelled with [H-3]Tyr(1)-D-Ala(2)-MePhe(4)-Gly-ol, [H-3]DAMGO and [H-3]Ile(5,6 )deltorphin, respectively. All of the new derivatives displayed highly attenuated binding to both receptor types, albeit the decrease in the ir potency seemed to be less in the case of 6 binding. Trans position of the beta-amino groups resulted in higher binding affinities than th at of the corresponding cis isomers, the latter being more flexible th an the former. It is concluded that conformational constraints caused either by a rigid ring structure or cis isomers instead of D-Ala(2) in dermorphin-derived peptides are unfavourable for binding activity to either opioid receptors. We propose that interaction of the larger hep tapeptide derivatives of dermorphins with the mu receptor is distinct from that of the tetrapeptide morphiceptin.