title: Dermorphin and deltorphin heptapeptide analogues: replacement of Phe residue by Dmp greatly improves opioid receptor affinity and selectivity.
abstract: The usefulness of 2,6-dimethylphenylalanine (Dmp) as a Phe surrogate in two opioid peptides, dermorphin (DM) and deltorphin II (DT), was investigated. Compared to DM, [L-Dmp(3)]DM (1) showed a 170-fold increase in mu affinity and only a 4-fold increase in delta affinity, resulting in a 40-fold improvement in mu receptor selectivity. Compared to DT, [L-Dmp(3)]DT (3) showed a 22-fold increase in delta affinity and somewhat of a loss in mu affinity, and consequently a marked (75-fold) improvement in delta receptor selectivity. The D-Dmp replacement, however, resulted in a great loss in receptor selectivity in each of the peptides. The specific receptor interactions of 1 and 3 were confirmed by in vitro bioassays. Analogues 1 and 3 seem to be useful as pharmacological tools for the study of opioid systems.
authors.affiliation: Tohoku Pharmaceutical University, 4-1 Komatsushima 4-chome, Aoba-ku, 981-8558, Sendai, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ambo
authors.forename: Harumi
authors.initials: H
authors.lastname: Murase
authors.forename: Hideko
authors.initials: H
authors.lastname: Niizuma
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Ouchi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
mesh_terms: D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D006168:Guinea Pigs; D020128:Inhibitory Concentration 50; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000502:physiology; D009292:Narcotic Antagonists; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018847:Opioid Peptides; D010649:Phenylalanine / Q000031:analogs & derivatives*; D011485:Protein Binding; D011957:Receptors, Opioid / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C427023:2',6'-dimethylphenylalanine; D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009842:Oligopeptides; D018847:Opioid Peptides; D011957:Receptors, Opioid; C059567:deltorphin; C030058:dermorphin; D010649:Phenylalanine