PROPERTIES OF TAN-67, A NONPEPTIDIC DELTA-OPIOID RECEPTOR AGONIST, AT CLONED HUMAN DELTA-OPIOID AND MU-OPIOID RECEPTORS

2-methyl-4a alpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a alpha-octahydro-quinolino[2,3,3-g]isoquinoline (TAN-67) is a nonpeptidic delta-opioid receptor agonist. This report describes its receptor binding affinity and agonist potency at human and mouse delta and mu-opioid receptors. The binding affinities of TAN-67 and the cyclic enkephalin analog, [D-Pen(2), 4'-Cl-Phe(4), D-Pen(5)]enkephalin (pCI-DPDPE) were measured by radioligand binding inhibition studies at mouse and human variants of the delta and mu-opioid receptor using [H-3]Naltrindole and [H-3]o-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2, respectively. TAN-67 showed high binding affinity (K-i = 0.647 nM) at the human delta-opioid receptor and high delta-opioid receptor binding selectivity (> 1000-fold) relative to the human mu-opioid receptor. TAN-67 also showed high potency (EC(50) = 1.72 nM) for the inhibition of forskolin-stimulated cAMP accumulation at human delta-opioid receptors expressed by intact Chinese hamster ovary cells but low potency (EC(50) = 1520 nM) at human mu-opioid receptors expressed by intact B82 mouse fibroblast cells. The results show that TAN-67 has similar binding affinities, selectivity and potencies as pCI-DPDPE at human delta and mu-opioid receptors. These results combined with the nonpeptidic structure of TAN-67 suggest that this compound has therapeutic potential as a delta-opioid receptor agonist.