Essential structure of opioid κ receptor agonist nalfurafine for binding to κ receptor 1: Synthesis of decahydroisoquinoline derivatives and their pharmacologies

Article abstract of DOI:10.1248/cpb.c12-00336

On the basis of the three-dimensional pharmacophore model of opioid κ agonists, we simplified the structure of nalfurafine (selective κ agonist) to find the essential structural moieties for binding the opioid receptors, especially κ receptor type. As a result, we found that the trans-fused decahydroisoquinoline derivatives without a phenol ring bound the opioid receptor in micromolar order and that both the amide side chain and the nitrogen substituted by the cyclopropylmethyl group were indispensable moieties for eliciting the κ selectivity. The simple decahydroisoquinoline without amide side chain also bound the opioid receptor without receptor type selectivity, suggesting that the message-address concept would be applicable to even these simple derivatives. These findings that the simple decahydroisoquinoline derivatives showed the affinities for the opioid receptors, especially some of the compounds showed κ selectivity, are the first example in the opioid field.

Full text of DOI:10.1248/cpb.c12-00336

August 2012
Communication to the Editor
Chem. Pharm. Bull. 60(8) 945–948 (2012)
945
hypothesis that in the active conformation of nalfurafine (Fig.
2), the C-ring would assume the boat form, thereby elevating
the amide side chain to bind the κ receptor.4,5,21,22) Based on
this hypothesis, we designed and synthesized KNT-63 with
an oxabicyclo[2.2.2]octane skeleton (Fig. 1), and confirmed
its high affinity for the κ receptor.5) We also proposed a new
three-dimensional pharmacophore model applicable to some
κ agonists with various chemotypes.21,22) Our new pharmaco-
phore model of κ agonists supported the proposed active con-
formation of nalfurafine and indicated that the binding modes
of κ agonists to the κ receptor could be classified into four
types. Nalfurafine belongs to binding mode type I, whereas
U-50,488H represents binding mode types II or III (Fig. 3). On
the basis of the model, we attempted to identify the essential
structural features of nalfurafine required for binding to the
κ receptor. From the view point of the message-address con-
cept,23–26) which is a useful guideline for designing selective
ligands for the opioid receptor types, the binding mode type
II seemed to resemble a binding pattern for the message part,
i.e., the μ antagonist naltrexone. So, we focused on the binding
mode type III and compared the conformations of nalfurafine
and U-50,488H (Fig. 3B) to identify two common structural
moieties: a basic nitrogen and an amide side chain. These ob-
servations prompted us to design simple decahydroisoquino-
line derivatives 1 (Fig. 4) which contain the same structures
as nalfurafine, but without the phenol ring moiety. Herein, we
report the synthesis of the designed decahydroisoquinoline
derivatives and the evaluation of their binding affinities for the
opioid receptor types.
Essential Structure of Opioid κ
Receptor Agonist Nalfurafine for
Binding to κ Receptor 1: Synthesis of
Decahydroisoquinoline Derivatives and
Their Pharmacologies
Hiroshi Nagase,* Satomi Imaide, Takaaki Yamada,
Shigeto Hirayama, Toru Nemoto, Noriyuki Yamaotsu,
Shuichi Hirono, and Hideaki Fujii
School of Pharmacy, Kitasato University; 5–9–1 Shirokane,
Minato-ku, Tokyo 108–8641, Japan.
Received April 13, 2012; accepted May 14, 2012
On the basis of the three-dimensional pharmacophore
model of opioid κ agonists, we simplified the structure of na-
lfurafine (selective κ agonist) to find the essential structural
moieties for binding the opioid receptors, especially κ recep-
tor type. As a result, we found that the trans-fused decahy-
droisoquinoline derivatives without a phenol ring bound the
opioid receptor in micromolar order and that both the amide
side chain and the nitrogen substituted by the cyclopropyl-
methyl group were indispensable moieties for eliciting the κ
selectivity. The simple decahydroisoquinoline without amide
side chain also bound the opioid receptor without receptor
type selectivity, suggesting that the message-address concept
would be applicable to even these simple derivatives. These
findings that the simple decahydroisoquinoline derivatives
showed the affinities for the opioid receptors, especially some
of the compounds showed κ selectivity, are the first example
in the opioid field.
The designed compound 1 (X=H) was prepared from
piperidone 2 (Chart 1). Piperidone 2 was converted to α,β-
unsaturated ketone 5 by condensation with dimethyl carbon-
ate and subsequent Robinson annulation.27,28) Birch reduction
of 5 afforded trans-fused decahydroisoquinolinone 6.28) The
target compounds 9 were obtained from 6 as a mixture of
Key words opioid; κ receptor; decahydroisoquinoline; nalfu-
rafine; three-dimensional pharmacophore model
Three types of opioid receptors (μ, δ, κ) are now well es- 6α- and 6β-amides via exchange of N-substituent, deac-
tablished not only by pharmacological studies but also by mo- etalyzation reductive amination, and following acylation. The
lecular biological studies.1) Narcotic addiction is believed to be corresponding N-methyl derivatives 10 (Fig. 5) were also
derived from the μ receptor type, and therefore δ and κ types synthesized by the same manner from 6. The synthesis of the
are promising drug targets for analgesics without addiction. designed compounds 1 with an angular hydroxy group (X=
To obtain ideal analgesics without addiction and other side OH) commenced with tetrahydroisoquinoline 11 prepared by
effects derived from the μ receptor, we have synthesized vari- the reported method29) (Chart 2). Enol ether 12 prepared from
ous kinds of naltrexone derivatives and have reported selective 11 by Birch reduction was acylated and hydrolyzed to give
ligands for κ2–9) and δ10–14) receptors. Quite recently, one of
our designed κ selective agonists, nalfurafine hydrochloride
(TRK-820,2,3,6,8,9) Fig. 1), was launched in Japan as an antipru-
ritic for patients undergoing dialysis.6,8,9)
Although many arylacetamide derivatives such as U-
50,488H15,16) (Fig. 1) and U-69,59317) were synthesized and
developed as κ agonists, all of these derivatives were elimi-
nated from clinical trials as not only analgesics but also as
antipruritics because of their serious side effects like psy-
chotomimetic and aversive reactions.18,19) In contrast, nalfu-
rafine has neither aversive nor addictive effects.20) Our interest
in the differences in the pharmacological effects between
nalfurafine and the arylacetamide derivatives led us to con-
duct a detailed structure activity relationship investigation of
nalfurafine derivatives. From these studies, we developed the
Fig. 1. Structures of Nalfurafine Hydrochloride, U-50,488H, and
The authors declare no conflict of interest.
KNT-63
*To whom correspondence should be addressed. e-mail: nagaseh@pharm.kitasato-u.ac.jp
© 2012 The Pharmaceutical Society of Japan

946
Vol. 60, No. 8
Fig. 4. Structure of the Designed Decahydroisoquinoline 1
Fig. 2. Proposed Active Conformation of Nalfurafine Binding to the κ
Receptor
Fig. 5. Structure of N-Methyldecahydroisoquinoline Derivatives 10
Fig. 3. (A) Superimposition of Active Conformation of Nalfurafine (Binding Mode Type I, Green) and U-50,488H (Binding Mode Type II, White)
and (B) Superimposition of Active Conformation of Nalfurafine (Binding Mode Type I, Green) and U-50,488H (Binding Mode Type III, White)
Reagents and conditions: i) NaH, CO(OMe)2, toluene, reflux, 57%; ii) methyl vinyl ketone, H2O, rt, 63%; iii) K2CO3, H2O, reflux, 34%; iv) Li, NH3 (liq.), EtOH,
−78°C, 40%; v) α-chloroethyl chloroformate, K2CO3, (CHCl2)2, reflux; vi) MeOH, reflux, 53% from 6; vii) c-PrCHO, NaBH3CN, AcOH, CH2Cl2, 0°C to rt; viii) 1M
HCl, 100°C, 36% from 7; ix) MeNH2·HCl, NaBH3CN, MeOH, reflux; x) 3-(furan-3-yl)acryloyl chloride, Et3N, CH2Cl2, 0°C, 9a: 14% from 8, 9b: 26% from 8. CPM:
cyclopropylmethyl.
Chart 1
β,γ-unsaturated ketone 13.28) The treatment of 13 with mCPBA angular aryl group exhibited κ opioid receptor affinities and
provided α,β-unsaturated ketone 14 with an angular hydroxy selectivities.30–32) The angular hydroxy group in nalfurafine
group, and following hydrogenation of 14 afforded trans- and significantly influenced the κ selectivity,3,8) whereas the angu-
cis-fused decahydroisoquinolinones 15 and 16. The target lar substituent (H or OH) in decahydroisoquinoline derivatives
compounds 19 were obtained from trans-fused 15 via reduc- 9 and 19 had minimal influence in the κ selectivity. Despite
tive amination, reduction of amide, and subsequent acylation.
the presence of the same amide side chain with the same
The binding affinities of the prepared compounds for the configuration as that of nalfurafine, the 6β-amide isomers
opioid receptor types were evaluated with competitive binding 9b and 19b showed worse affinities and selectivities for the
assays (Table 1). The assays were performed by a modification κ receptor than the corresponding 6α-amide compounds 9a
of a previously reported procedure.14)
and 19a. This improved binding might result from the par-
Although all the synthesized compounds showed weak ticipation of the boat conformer A′ of the 6α-amides which is
binding affinities for the opioid receptors (micromolar order favored over the chair conformer A by a steric repulsion due
affinities), N-cyclopropylmethyl (CPM) derivatives 9 and 19 to 1,3-interaction in A (Fig. 6). The amide side chain in the
had significant affinities and selectivities for the κ receptor. To conformer A′ could be oriented toward the upper side to more
the best of our knowledge, this was the first result that such effectively bind to the κ receptor and this orientation is not
simple trans-decahydroisoquinoline derivatives without an possible in the stable chair conformer B of the 6β-amides. The

August 2012
947
Reagents and conditions: i) Li, NH3 (liq.), EtOH, THF, −78°C, 80%; ii) c-PrCOCl, Et3N, CH2Cl2, rt; iii) 0.5M HCl, THF, rt, 75% from 12; iv) mCPBA, CH2Cl2, rt,
70%; v) H2, Pd/C, THF, rt, 15: 49%, 16: 47%; vi) MeNH2·HCl, NaBH3CN, MeOH; vii) LiAlH4, THF, rt, 18a: 24% from 15, 18b: 19% from 15; viii) 3-(furan-3-yl)acry-
loyl chloride, Et3N, CH2Cl2, 0°C, 19a: 93% from 18a, 19b: 93% from 18b. CPM: cyclopropylmethyl.
Chart 2
Table 1. Binding Affinities of Decahydroisoquinolines 9, 10, 18, and 19
for Opioid Receptor Typesa)
Ki (µM)
Compound
μb)
δc)
>100
>100
12.2
κd)
9a
9b
45.7
11.0
19.2
>100
>100
9.82
20.6
10a
10b
18a
18b
19a
19b
>100
85.2
32.1
36.1
15.3
36.3
>100
>100
>100
>100
>100
>100
11.4
Fig. 6. Conformers A and A′ of trans-Fused Decahydroisoquinoline-6α-
amides 9a and 19a, and Conformer B of trans-Fused Decahydroiso-
quinoline-6β-amides 9b and 19b
19.1
a) Binding assays were carried out in duplicate (κ: cerebellum of guinea pig; μ
and δ: whole brain without cerebellum of mouse). b) [3H] DAMGO was used. c) [3H]
DPDPE was used. d) [3H] U-69,593 was used.
decahydroisoquinoline without an amide side chain could also
bind the opioid receptor without receptor type selectivity, sug-
trans-decahydroisoquinolines 9 and 19 showed noteworthy af- gesting that the message-address concept would be applicable
finities for the κ receptor, however their affinities were lower to even these simple derivatives. These findings that the sim-
than that of nalfurafine which displayed subnanomolar order ple decahydroisoquinoline derivatives showed the affinities for
affinity.9) These observations suggest that the phenol moiety the opioid receptor, especially with some of the compounds
plays an important role in elicitation of high affinity for the showing κ selectivity, are unprecedented in opioid research.
opioid receptor types but that it is not an indispensable part The outcomes are expected to contribute to the design of new
for binding to the κ receptor.33–37) The phenol functionality in κ opioid selective ligands.
nalfurafine would force the C-ring to assume a boat form and
effectively increase the population of the active conformation.
Acknowledgements We acknowledge the financial sup-
trans-Decahydroisoquinoline 18a without the amide side chain ports from Shorai Foundation for Science, Uehara Memorial
showed binding affinities for the all opioid receptor types but Foundation, and JSPS KAKENHI (23590133) [Grant-in-Aid
no selectivity for the κ receptor was observed. It is remarkable for Scientific Research (C)]. We also acknowledge the Institute
that even the simple decahydroisoquinoline without amide side of Instrumental Analysis of Kitasato University, School of
chain exhibited affinity for each of the opioid receptor types Pharmacy for its facilities.
and that the message-address concept would also be applicable
to the decahydroisoquinoline derivatives. This result would
support the importance of the amide side chain for conferring
selectivity to the κ receptor binding. Compared to the N-CPM
derivatives 9, N-methyl derivatives 10 lost κ selectivities, con-
firming that the N-CPM substituent is preferable for elicitation
of the κ selectivity.
In conclusion, on the basis of the three-dimensional phar-
macophore model of κ agonists, we simplified the structure
of nalfurafine to find the essential structural determinants for
binding the opioid receptor, especially the κ receptor type. As
a result, we found that the trans-fused decahydroisoquinoline
derivatives without a phenol ring bound the opioid receptor
in the micromolar order and that both the amide side chain
and the nitrogen substituted by the CPM group were indis-
pensable moieties for eliciting the κ selectivity. The simple
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