RATIONAL DRUG DESIGN AND SYNTHESIS OF A HIGHLY SELECTIVE NONPEPTIDE DELTA-OPIOID AGONIST, 1,2,3,4,4A,5,12,12A-OCTAHYDROPYRIDO[3,4-B]ACRIDINE (TAN-67)

We designed highly selective non-peptide agonists for the delta-opioid receptor. On the basis of the ''message-address'' concept in this fie ld and the accessory site hypothesis, a novel class of heterocycle-fus ed octahydroisoquinoline derivatives were synthesized. One of these co mpounds ,2,3,4,4a,5,12,12a-octahydropyrido[3,4-b]acridine, TAN-67 (2)] showed high selectivity for the delta-opioid receptor (K-i=1.12 nM) i n guinea-pig cerebrum with a 2070-fold lower affinity for the mu-opioi d receptor and a 1600-fold lower affinity for the kappa-opioid recepto r. TAN-67 was a potent delta-opioid receptor agonist with an IC,, valu e of 6.61 nM in the mouse vas deferens assay that was reversed by nalt rindole (NTI) (K-e=0.21). Moreover, TAN-67,vas shown to have antinocic eptive activity following subcutaneous administration in the mouse ace tic acid abdominal constriction assay that was antagonized by NTI (del ta(1)- and delta(2)-antagonist) and 7-benzylidinenaltrexone (delta(1)- antagonist), but not by naltriben (delta(2)-antagonist). This systemic ally applicable non-peptide agonist will be useful for elucidating the pharmacological properties of the delta-opioid receptor.