Rational drug design of δ opioid receptor agonist TAN-67

Abstract

A selective nonpeptidic δ 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-octahydropyrido[3,4-b]acridine was designed from the selective δ opioid receptor antagonist NTI on the basis of the message-address concept and the accessory site theory. (-)-TAN-67 is a potent and selective δ1 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-oxodecahydroisoquinoline, the important intermediate ketone of TAN-67 synthesis were also described.