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 pep-tide-receptor interactions had led to the assumption that µ-and-receptors are located in anionic and cationic membrane compartments, respectively, and to the predictionthat positively charged opioid receptor ligands should display µ-receptor selectivity. To assess the validity of thismodel, we synthesized a series of dermorphin analogues carrying a net positive charge and tested them in µ-and-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-(l-4) tetrapeptide analogues produced an enhancement of µ-receptor affinity and a progressive decrease in-receptor affinity, resulting in increasingly higher µ-receptor selectivity. The most selective compound was [D-Arg2, Lys4] dermorphin-(l-4)-amide (DALDA), showing a selectivity ratio (Kf/Kf= 11400) more than 10 times higher than that of DAGO (Kf/Kf= 1050) and, thus, displaying unprecedented µ-receptor specificity. Because of its high positive charge (3+), DALDA may be particularly useful as a very specific agonist for studying peripheral µ-receptor interactions.