Potent Dmt-Tic pharmacophoric delta- and mu-opioid receptor antagonists.
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.
Li
Tingyou
T
The Graduate School of Food and Medicinal Sciences and Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Nishi-ku, Kobe 651-2180, Japan.
Fujita
Yoshio
Y
Shiotani
Kimitaka
K
Miyazaki
Anna
A
Tsuda
Yuko
Y
Ambo
Akihiro
A
Sasaki
Yusuke
Y
Jinsmaa
Yunden
Y
Marczak
Ewa
E
Bryant
Sharon D
SD
Salvadori
Severo
S
Lazarus
Lawrence H
LH
Okada
Yoshio
Y
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
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