Rational Drug Design and Synthesis of a Highly Selective Nonpeptide δ-Opioid Agonist, (4aS^*, 12aR^*)-4a-(3-Hydroxyphenyl)-2-methyl-1,2,3,4,4a, 5,12,12a-octahydropyrido[3,4-b]acridine (TAN-67)

We designed highly selective non-peptide agonists for the δ-opioid receptor. On the basis of the "message-address" concept in this field and the accessory site hypothesis, a novel class of hetericycle-fused octahydroisoquinoline derivatives were synthesized. One of these compounds (4aS*, 12aR*)-4a-(3-hydroxyphenyl)-2-methyl-1, 2, 3, 4, 4a, 5, 12, 12a-octahydropyrido[3, 4-b]acridine, TAN-67 (2)] showed high selectivity for the δ-opioid receptor (Ki=1.12 nM) in guinea-pig cerebrum with a 2070-fold lower affinity for the μ-opioid receptor and a 1600-fold lower affinity for the К-opioid receptor. TAN-67 was a potent δ-opioid receptor agonist with an IC50 value of 6.61 nM in the mouse vas deferens assay that was reversed by naltrindole (NTI) (Ke=0.21). Moreover, TAN-67 was shown to have antinociceptive activity following subcutaneous administration in the mouse acetic acid abdominal constriction assay that was antagonized by NTI (δ1-and δ2-antagonist) and 7-benzylidinenaltrexone (δ1-antagonist), but not by naltriben (δ2-antagonist). This systemically applicable non-peptide agonist will be useful for elucidating the pharmacological properties of the δ-opioid receptor.