title: Potent Dmt-Tic pharmacophoric delta- and mu-opioid receptor antagonists.
abstract: A series of dimeric Dmt-Tic (2',6'-dimethyl-L-tyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) analogues (8-14, 18-22) were covalently linked through diaminoalkane and symmetric or asymmetric 3,6-diaminoalkyl-2(1H)-pyrazinone moieties. All the compounds exhibited high affinity for both delta-opioid receptors [Ki(delta) = 0.06-1.53 nM] and mu-opioid receptors [Ki(mu) = 1.37-5.72 nM], resulting in moderate delta-receptor selectivity [Ki(mu)/Ki(delta) = 3-46]. Regardless of the type of linker between the Dmt-Tic pharmacophores, delta-opioid-mediated antagonism was extraordinarily high in all analogues (pA2 = 10.42-11.28), while in vitro agonism (MVD and GPI bioassays) was essentially absent (ca. 3 to >10 microM). While an unmodified N-terminus (9, 13, 18) revealed weak mu-opioid antagonism (pA2 = 6.78-6.99), N,N'-dimethylation (21, 22), which negatively impacts on mu-opioid-associated agonism (Balboni et al., Bioorg. Med. Chem. 2003, 11, 5435-5441), markedly enhanced mu-opioid antagonism (pA2 = 8.34 and 7.71 for 21 and 22, respectively) without affecting delta-opioid activity. These data are the first evidence that a single dimeric opioid ligand containing the Dmt-Tic pharmacophore exhibits highly potent delta- and mu-opioid antagonist activities.
authors.affiliation: The Graduate School of Food and Medicinal Sciences and Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Nishi-ku, Kobe 651-2180, Japan.
authors.forename: Tingyou
authors.initials: T
authors.lastname: Li
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Fujita
authors.forename: Kimitaka
authors.initials: K
authors.lastname: Shiotani
authors.forename: Anna
authors.initials: A
authors.lastname: Miyazaki
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ambo
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Yunden
authors.initials: Y
authors.lastname: Jinsmaa
authors.forename: Ewa
authors.initials: E
authors.lastname: Marczak
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Bryant
authors.forename: Severo
authors.initials: S
authors.lastname: Salvadori
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Lazarus
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Okada
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D003959:Diamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: C507634:1,6-bis(N,N-dimethyl-2',6'-dimethyltyrosyl-1,2,3,4-tetrahydro-3-isoquinolineamido)hexane; C446951:2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; C507635:3,6-bis(N,N-dimethyl-2',6'-dimethyltyrosyl-1,2,3,4-tetrahydro-3-isoquinolineamidopropyl)-2(1H)-pyrazinone; D003959:Diamines; D004151:Dipeptides; D008024:Ligands; D010455:Peptides; D011719:Pyrazines; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D044005:Tetrahydroisoquinolines