| Abstract
| - A series of dimeric Dmt-Tic (2‘,6‘-dimethyl-l-tyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid) analogues (8−14, 18−22) were covalently linked through diaminoalkane and symmetricor asymmetric 3,6-diaminoalkyl-2(1H)-pyrazinone moieties. All the compounds exhibited highaffinity 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 thetype of linker between the Dmt-Tic pharmacophores, δ-opioid-mediated antagonism wasextraordinarily high in all analogues (pA2 = 10.42−11.28), while in vitro agonism (MVD andGPI 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 21and 22, respectively) without affecting δ-opioid activity. These data are the first evidence thata single dimeric opioid ligand containing the Dmt-Tic pharmacophore exhibits highly potentδ- and μ-opioid antagonist activities.
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