In the present work, eight conformationally constrained analogues of the μ specific opioid peptide dermorphin were synthesized by replacing D-Ala2 with stereoisomers of β-amino-cycloalkane or cyctoalkene carboxylic acids. The resulting peptides were tested for their potency to μ and δ opioid binding sites of rat brain membranes labelled with [3H]Tyr1-D-Ala2- MePhe4-Gly-ol, [3H]DAMGO and [3H]Ile5,6deltorphin, respectively. All of the new derivatives displayed highly attenuated binding to both receptor types, albeit the decrease in their potency seemed to be less in the case of δ binding. Trans position of the β-amino groups resulted in higher binding affinities than that of the corresponding cis isomers, the latter being more flexible than the former. It is concluded that conformational constraints caused either by a rigid ring structure or cis isomers instead of D-Ala2 in dermorphin-derived peptides are unfavourable for binding activity to either opioid receptors. We propose that interaction of the larger heptapeptide derivatives of dermorphins with the μ receptor is distinct from that of the tetrapeptide morphiceptin.
ASJC Scopus subject areas
- Endocrine and Autonomic Systems
- Cellular and Molecular Neuroscience