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 ä-opioid receptors [Ki(ä) ) 0.06-1.53 nM] and í-opioid receptors [Ki(í) ) 1.37- 5.72 nM], resulting in moderate ä-receptor selectivity [Ki(í)/Ki(ä) ) 3-46]. Regardless of the type of linker between the Dmt-Tic pharmacophores, ä-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 íM). While an unmodified N-terminus (9, 13, 18) revealed weak í-opioid antagonism (pA2 ) 6.78-6.99), N,N¢-dimethylation (21, 22), which negatively impacts on í-opioid-associated agonism (Balboni et al., Bioorg. Med. Chem. 2003, 11, 5435-5441), markedly enhanced í-opioid antagonism (pA2 ) 8.34 and 7.71 for 21 and 22, respectively) without affecting ä-opioid activity. These data are the first evidence that a single dimeric opioid ligand containing the Dmt-Tic pharmacophore exhibits highly potent ä- and í-opioid antagonist activities.
Potent Dmt-Tic pharmacophoric delta- and mu-opioid receptor antagonists
SALVADORI, Severo;
2005
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 ä-opioid receptors [Ki(ä) ) 0.06-1.53 nM] and í-opioid receptors [Ki(í) ) 1.37- 5.72 nM], resulting in moderate ä-receptor selectivity [Ki(í)/Ki(ä) ) 3-46]. Regardless of the type of linker between the Dmt-Tic pharmacophores, ä-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 íM). While an unmodified N-terminus (9, 13, 18) revealed weak í-opioid antagonism (pA2 ) 6.78-6.99), N,N¢-dimethylation (21, 22), which negatively impacts on í-opioid-associated agonism (Balboni et al., Bioorg. Med. Chem. 2003, 11, 5435-5441), markedly enhanced í-opioid antagonism (pA2 ) 8.34 and 7.71 for 21 and 22, respectively) without affecting ä-opioid activity. These data are the first evidence that a single dimeric opioid ligand containing the Dmt-Tic pharmacophore exhibits highly potent ä- and í-opioid antagonist activities.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
