Rational drug design and synthesis of a highly selective nonpeptide delta-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 delta-opioid receptor. On the basis of the "message-address" concept in this field and the accessory site hypothesis, a novel class of heterocycle-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 delta-opioid receptor (Ki = 1.12 nM) in guinea-pig cerebrum with a 2070-fold lower affinity for the mu-opioid receptor and a 1600-fold lower affinity for the kappa-opioid receptor. TAN-67 was a potent delta-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 (delta 1- and delta 2-antagonist) and 7-benzylidinenaltrexone (delta 1-antagonist), but not by naltriben (delta 2-antagonist). This systemically applicable non-peptide agonist will be useful for elucidating the pharmacological properties of the delta-opioid receptor.
Nagase
H
H
Basic Research Laboratories, Toray Industries, Inc., Kanagawa, Japan.
Kawai
K
K
Hayakawa
J
J
Wakita
H
H
Mizusuna
A
A
Matsuura
H
H
Tajima
C
C
Takezawa
Y
Y
Endoh
T
T
D019342:Acetic Acid; D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D015195:Drug Design; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000139:chemically induced / Q000517:prevention & control; D010147:Pain Measurement / Q000187:drug effects; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000819:agonists*
D000701:Analgesics, Opioid; D008024:Ligands; D011804:Quinolines; D017465:Receptors, Opioid, delta; C094142:TAN 67; D019342:Acetic Acid