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

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