Synthesis of optically active TAN-67, a highly selective delta opioid receptor agonist, and investigation of its pharmacological properties.
We have synthesized the nonpeptidic highly selective delta opioid receptor agonist, (+/-)-TAN-67, (4aS*, 12aR*)-4a-(3-hydroxyphenyl)-2-methyl-1,2,3,4,4a,5,12,12a-octahydropyrido [3,4-b] acridine. In spite of high potent agonist activity for the delta opioid receptor in in vitro assay, (+/-)-TAN-67 afforded no analgesic activity in the mouse warm-plate test. This result led us to separate (+/-)-TAN-67 into optically pure compounds. Each enantiomer of racemic TAN-67 was synthesized from the corresponding optically active 6-oxodecahydroisoquinoline which was obtained by fractional recrystallization of its optically pure di-p-toluoyl tartaric acid salt. In bioassay using mouse vas deferens, (-)-TAN-67 showed full agonist activity (IC50 = 3.65 nM). On the other hand, (+)-TAN-67 showed almost no agonist activity, but interestingly afforded hyperalgesic activity in vivo (i.t. injection).
Fujii
H
H
Pharmaceutical Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa, Japan.
Kawai
K
K
Kawamura
K
K
Mizusuna
A
A
Onoda
Y
Y
Murachi
M
M
Tanaka
T
T
Endoh
T
T
Nagase
H
H
D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D008297:Male; D051379:Mice; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000819:agonists*; D014649:Vas Deferens / Q000187:drug effects
D000700:Analgesics; D011804:Quinolines; D017465:Receptors, Opioid, delta; C094142:TAN 67