title: Dermorphin analogues carrying an increased positive net charge in their "message" domain display extremely high mu opioid receptor selectivity.
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 (Ki delta/Ki mu = 11,400) more than 10 times higher than that of DAGO (Ki delta /Ki 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.
authors.affiliation: Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Quebec, Canada.
authors.forename: P W
authors.initials: PW
authors.lastname: Schiller
authors.forename: T M
authors.initials: TM
authors.lastname: Nguyen
authors.forename: N N
authors.initials: NN
authors.lastname: Chung
authors.forename: C
authors.initials: C
authors.lastname: Lemieux
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D018847:Opioid Peptides; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects* / Q000378:metabolism; D017450:Receptors, Opioid, mu; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; D018847:Opioid Peptides; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; C030058:dermorphin