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Potent Dmt-Tic Pharmacophoric δ- and μ-Opioid Receptor Antagonists

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journal contribution
posted on 15.12.2005, 00:00 by Tingyou Li, Yoshio Fujita, Kimitaka Shiotani, Anna Miyazaki, Yuko Tsuda, Akihiro Ambo, Yusuke Sasaki, Yunden Jinsmaa, Ewa Marczak, Sharon D. Bryant, Severo Salvadori, Lawrence H. Lazarus, Yoshio Okada
A series of dimeric Dmt-Tic (2‘,6‘-dimethyl-l-tyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) analogues (814, 1822) were covalently linked through diaminoalkane and symmetric or asymmetric 3,6-diaminoalkyl-2(1H)-pyrazinone moieties. All the compounds exhibited high affinity for both δ-opioid receptors [Ki(δ) = 0.06−1.53 nM] and μ-opioid receptors [Ki(μ) = 1.37−5.72 nM], resulting in moderate δ-receptor selectivity [Ki(μ)/Ki(δ) = 3−46]. Regardless of the type of linker between the Dmt-Tic pharmacophores, δ-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 μM). While an unmodified N-terminus (9, 13, 18) revealed weak μ-opioid antagonism (pA2 = 6.78−6.99), N,N-dimethylation (21, 22), which negatively impacts on μ-opioid-associated agonism (Balboni et al., Bioorg. Med. Chem. 2003, 11, 5435−5441), markedly enhanced μ-opioid antagonism (pA2 = 8.34 and 7.71 for 21 and 22, respectively) without affecting δ-opioid activity. These data are the first evidence that a single dimeric opioid ligand containing the Dmt-Tic pharmacophore exhibits highly potent δ- and μ-opioid antagonist activities.