The pharmacological profile of delta opioid receptor ligands, (+) and (-) TAN-67 on pain modulation.
We designed the nonpeptidic highly selective delta opioid receptor agonist on the basis of message address concept and the accessory site theory and synthesized (+/-) TAN-67. In spite of highly potent agonistic activity in in vitro assay, (+/-) TAN-67 (racemate) afforded a weak antinociceptive effect in the mouse tail-flick test. This result led us to separate (+/-) TAN-67 to optical pure compounds, (+) and (-) TAN-67. An i.t.-treatment with (-) TAN-67 produced profound antinociceptive effects through specifically acting on delta1 receptors. Unlike (-) TAN-67, i.t.-administered (+) TAN-67 displayed dose-related nociceptive behaviors such as scratching, biting and licking. The effect of (+) TAN-67 was blocked by i.t.-treatment with NTI (delta receptor antagonist) and (-) TAN-67 (delta1 receptor agonist), but not by morphine (mu receptor agonist). The mechanisms involved in spinal pain modulation induced by (+) and (-) TAN-67 were also described.
Nagase
H
H
Pharmaceutical Research Laboratories, Toray Industries Inc., Kanagawa, Japan. nagaseh@blab.toray.co.jp
Yajima
Y
Y
Fujii
H
H
Kawamura
K
K
Narita
M
M
Kamei
J
J
Suzuki
T
T
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006168:Guinea Pigs; D008024:Ligands; D051379:Mice; D008954:Models, Biological; D009619:Nociceptors / Q000187:drug effects*; D010146:Pain / Q000517:prevention & control; D011804:Quinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000819:agonists*; D013237:Stereoisomerism
D000700:Analgesics; D008024:Ligands; D011804:Quinolines; D017465:Receptors, Opioid, delta; C094142:TAN 67