Rational drug design of δ opioid receptor agonist TAN-67

A selective nonpeptidic 3 opioid receptor agonist TAN-67, (4 aS*, 12 aR*)-4 a-(3-hydroxyphenyl) -2-methyl-1, 2, 3, 4, 4 a, 5, 12, 12 a-octabydropyrido [3, 4-b] acridine was designed from the selective 6 opioid receptor antagonist NTI on the basis of the message-address concept and the accessory site theory. (-)-TAN-67 is a potent and selective delta(1) opioid receptor agonist and showed profound antinociceptive effect, cardioprotective effect, and antiarrhythmic effect. On the contrary, (+)-TAN-67 induced hyperalgesia, which is the opposite effect of the antinociception. Optical resolution of racemic TAN-67 and the synthesis of (4 aS*, 8* aR*)-4 a-(3-methoxyphenyl)-2-methyl-6-oxodecahydioisoquinoline, the important intermediate ketone of TAN-67 synthesis were also described.