Table 4. Mouse formalin test initial phase and MOR assay of compounds 1, 15a, and 15b
MOR binding assay
Formalin test initial phase
(% inhibition at 30 mg/kg)
MOR cAMP assay
MOR cAMP assay
Compound
EC50 (μM)b
Emax (%)c
IC50 (μM)a
(−)-1
15a
43
83
30
70
>100
>100
>100
13
19
18
>100
>100
15b
aBinding affinities (IC50) were obtained by the competitive displacement of radiolabeled [3H] diprenorphine. Morphine with an IC50 0.41 μM was used as a
positive control.
bCyclic adenine monophosphate (cAMP) assay was performed using human mu-opioid receptor (MOR)-expressing CHO cells. The EC50 of DAMGO, the
positive control, was 0.075 μM.
cEmax was calculated as the % of the response obtained with DAMGO.
In conclusion, we identified a novel compound, (5S)-6-methyl-
1,3,4,5,6,8-hexahydro-7H-2,5-methano[1,5]diazonino[7,8-
Furthermore, the compound exhibited weak hERG channel
inhibition and no MOR agonist activity. Although the mechanism
of action of DS54360155 is not completely understood, we
consider it a promising candidate compound for application as an
analgesic. Currently, studies on further derivatization of this series
of compounds and target identification are ongoing to understand
the mechanism of action, and the results will be reported in due
course.
b]indol-7-one sulfate salt 15a, derived from the natural product
conolidine. Compound 15a (DS54360155)18 has a unique and
original [5.2.1] bicyclic structure comprising an amide bond and a
pyrrolidine ring. The compound exhibited potent analgesic
efficacy following oral administration in mice, as revealed by both
the acetic acid-induced writhing test and formalin test.
References and notes
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aminopyrrolidine (>97.0 ee%) which were purchased
from Tokyo Chemical Industry Co., Ltd.
11. (S) and (R)-1-(tert-butoxycarbonyl)-3-aminopiperidine
(>97 ee%) were purchased from FUJIFILM Wako Pure
Chemical Corporation.
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(>98.0 ee%) and (3R)-(-)-1-(tert-butoxycarbonyl)-3-
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Singh L. Br J Pharmacol. 1997;121;1513.
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18. See supporting information for details of the
experimental procedure of 15a.
Graphical Abstract
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Discovery of a novel bicyclic compound,
DS54360155, as an orally potent analgesic
without mu opioid receptor agonist activity
Leave this area blank for abstract info.
Tsuyoshi Arita, Masayoshi Asano, Yuki Domon, Kazufumi Kubota, Nobuo Machinaga, Kousei Shimada
N
Analgesic activity against
acetic acid-induced writhing ED50 12 mg/kg
N
N
H
Formalin test initial phase
83% inhibition at 30 mg/kg
O
DS54360155