Dermorphin analogs carrying an increased positive net charge in their "message" domain display extremely high .mu.-opioid receptor selectivity

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Abstract
According to the membrane compartment concept the receptor specificity of ligands is based not only on ligand-receptor complementarity but also on specific ligand-membrane interactions. Elaboration of this concept for opioid peptide-receptor interactions had led to the assumption that .mu.- and .delta.-receptors are located in anionic and cationic membrane compartments, respectively, and to the prediction that positively charged opioid receptor ligands should display .mu.-receptor selectivity. To assess the validity of this model, we synthesized a series of dermorphin analogues carrying a net positive charge and tested them in .mu.- and .delta.-receptor representative binding assays and bioassays. Some but not all of the prepared compounds showed the receptor-selectivity profile expected on the basis of the membrane compartment concept. In particular, gradual augmentation of the positive charge from 1+ to 3+ in a series of dermorphin-(1-4) tetrapeptide analogues produced an enhancement of .mu.-receptor affinity and a progressive decrease in .delta.-receptor affinity, resulting in increasingly higher .mu.-receptor selectivity. The most selective compound was [D-Arg2-,Lys4]dermorphin-(1-4)-amide (DALDA), showing a selectivity ratio (K1.delta./K1.mu. = 11,400) more than 10 times higher than that of DAGO (K1.delta./K1.mu. = 1050) and, thus, displaying unprecedented .mu.-receptor specificity. Because of its high positive charge (3+), DALDA may be particularly useful as a very specific agonist for studying peripheral .mu.-receptor interactions.