Properties of TAN-67, a nonpeptide δ-opioid receptor agonist, at cloned human δ-and μ-opioid receptors

Abstract

2-methyl-4a α(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a α-octahydro-quinolino[2,3,3-g]isoquinoline (TAN-67) is a nonpeptidic δ-opioid receptor agonist. This report describes its receptor binding affinity and agonist potency at human and mouse δ and μ-opioid receptors. The binding affinities of TAN-67 and the cyclic enkephalin analog, [D-Pen², 4′-Cl-Phe⁴, D-Pen⁵]enkephalin (pCl-DPDPE) were measured by the radioligand binding inhibition studies at mouse and human variants of the δ and μ-opioid receptor using [³H]Naltrindole and [³H]D-Phe-$\text{Cys  Tyr  D  Trp  Orn  Thr  Pen}$-Thr-NH₂, respectively. TAN-67 showed high binding affinity (K_i = 0.647 nM) at the human δ-opioid receptor and high δ-opioid receptor binding selectivity (> 1000-fold) relative to the human μ-opioid receptor. TAN-67 also showed high potency (EC₅₀ = 1.72 nM) for the inhibition of forskolin-stimulated cAMP accumulation at human δ-opioid receptors expressed by intact Chinese hamster ovary cells but low potency (EC₅₀ = 1520 nM) at human μ-opioid receptors expressed by intact B82 mouse fibroblast cells. The results show that TAN-67 has similar binding affinities, selectivity and potencies as pCl-DPDPE at human δ and μ-opioid receptors. These results combined with the nonpeptidic structure of TAN-67 suggest that this compound has therapeutic potential as a δ-opioid receptor agonist.