The 14th (2014) Yamazaki-Teiichi Prize

Winner Biological Science & Technology

Design and Synthesis of Opioid Receptor Type
Selective Ligands and their Application to Drugs
Winner
Hiroshi Nagase
History
Mar.

Completed the doctoral course at the Graduate

1976

School of Science, Nagoya University

Apr.

Entered the Basic Research Laboratories, Toray

1976

Ind., Inc.

Apr.

Deputy Director, Basic Research Laboratories,

1997

Toray Ind., Inc.

Apr.

Director, Medical Research Center, Toray Ind.,

2001

Inc.

Apr.

Professor at Kitasato University School of

2004

Pharmacy

Apr.
2013

Professor at the International Institute for

Integrative Sleep Medicine (WPI), University of
Tsukuba
present

Reason for award

Although opium analogs (opioids), represented by morphine, have a strong
analgesic action and other distinguished pharmacological actions, they have
been used for late-stage cancer pain and other limited applications because
of their side effects, such as drug dependence. Dr. Hiroshi Nagase, who
focused attention on the fact that there are three types of receptors (, , )

in opioids in the cell surface, succeeded in finding the method for avoiding
the binding of receptors, which is the cause of drug dependence, and, at
the same time, developing antagonists with high selectivity for each of and
receptors (drug that binds itself to receptors to suppress the activity of
agonist) and selective agonists to receptor (drug that bind itself receptors
to show the activity). Nalfurafine, which is an agonist for receptor, in
particular, was the first drug in the world without drug dependence, and drug
aversive effect like hallucination, and auditory hallucination.
Nalfurafine is very effective in alleviating itching and has released many
kidney dialysis patients from intolerable pruritus. Dr. Nagase also found out
that the selective drugs for the opioid receptor types have a variety of
pharmacological actions, such as antitussive, antidepressant, anxiolytic,
anti-pollakiuria, antimalarial, and anticancer effects, and is cultivating a new
area for new opioid drug without dependence and aversion.
Due to the aforesaid reasons, Dr. Nagase will be an awardee of the 14th
Yamazaki-Teiichi Prize in biological science & technology.

Background of research and development

Although opioids, represented by morphine, have a strong analgesic action
and other distinguished pharmacological actions, they have been used for
limited applications because of their serious side effects, such as drug
dependence. Recently, however, it has been revealed that there are three
types of opioid receptors (, , ), and an agonist or antagonist with high
selectivity has been required for each type of receptor because of the
necessity to study the pharmacological actions of these three receptor types.
Professor Portoghese, ahead of other researchers, synthesized -FNA, which
is the irreversible receptor antagonist, and reported, as a result of the use
of this antagonist, that drug dependence was attributed to the receptor.
This report triggered fierce competition in the creation of a agonist in
pursuit of a dream analgesic.
At that time, I successfully synthesized a antagonist, nor-BNI, and
antagonist NTI based on the basic structure of naltrexone and applying the
message-address concept in collaboration with Professor Portoghese. Fullscale research in the three types of opioids began all over the world, using
these antagonists and the antagonist discovered by Professor Portoghese

(Figure 1). On the other hand, subtypes of the receptors were also
proposed, and I also succeeded in synthesizing antagonists for these
subtypes (1: BNTX, 2: NTB).

Fig. 1 Message-address concept and structures of the three antagonists

Achievements
Design and synthesis of opioid agonists
Competition in the development of agonists traces back to the report
of the world's first selective agonist, U-50488H, by Upjohn. That is,
pharmaceutical companies in the world developed compounds imitating
the structure of this U-50488H and heated up competition (Figure 2).
Although these U-50488H-type drugs yielded the great results of the
confirmation of analgesic actions and the separation of dependence,
they showed serious drug aversion (actions represented by hallucination
and auditory hallucination). The types of drugs shown in Figure 2 were
dropped out at the initial stage of clinical trials.
In the present research, I did not imitate the structure of Upjohn's
agonist and designed and synthesized an agonist with novel structure.
The accessory site theory was utilized for the design. To be specific, a

antagonist has lipophilic site called an accessory site whereas an agonist

has no the site and resulting in that the agonist has slim structure. Using
this theory, I synthesized an agonist with a slim structure without the
lipophilic site, and finally led to nalfurafine as a result of the optimization
of the obtained agonists (Figure 3).
Fortunately, this nalfurafine showed potent analgesic effect and became
the first drug to succeed in separating both dependence and aversion.
I further conducted clinical trial for application to postoperative pain, but
the trial confirmed a serious sedative action (drowsiness, wobble ) at the
dose which the analgesic effect was shown. For this reason, I gave up
the application of nalfurafine to postoperative pain.

Fig. 2 Structures of representative agonists developed in the world

Fig. 3 Accessory site theory and design and synthesis of agonist nalfurafine

Application to serious pruritus of kidney dialysis patients and

therapeutic effect to drug dependence
For the abovementioned reason, I examined another application of
nalfurafine, and obtained the information that kidney dialysis patients
suffered from serious pruritus. I performed animal tests and clinical trial
to determine whether nalfurafine was effective against it, and finally
succeeded in releasing it on the market as a therapeutic drug for
intractable pruritus. The agonists of competitors have still not been
released to the market because of the serious aversion. This nalfurafine
was also proven in a national project (Research in the clarification of
the mechanism of mental disorder induced by drug dependence) with
Professor Toshitaka Nabeshima (School of Medicine, Nagoya University)
and Professor Tsutomu Suzuki (Hoshi University) that it was effective
against to most of the addictive drugs, including methamphetamine,
morphine, cocaine, and nicotine. In addition, it was also revealed that
the inhibition of dopamine release in the nucleus accumbens led to inthis
effect.

Design and synthesis of agonists and finding of the antidepressant

and anxiolytic effects
Meanwhile, I also conducted in-depth research in receptor agonists,
and designed and synthesized the highly selective receptor agonists
TAN-67 and KNT-127, which were improved blood brain barrier
permeability than the former, designed by removing the accessory site
from the structure of NTI (Figure 4). Both of these agonists completely
separated serious side effects (convulsion, catalepsy), which were the
reasons why the development of another agonists of competitors could
not succeed, and the KNT-127 showed activity more than 100 times
higher than that of standard receptor agonists. In addition, I
discovered another agonists with novel structures, and these
compounds led us to find not only an analgesic effect, but
antidepressant and anxiolytic effects, and anti pollakiuria Highly
evaluated for its effects andthe usefulness, the present research is

adopted for A-STEP (Adaptable and Seamless Technology Transfer

Program through Target-driven R & D, seeds development type and high
risk challenge type: both of them are joint researches with Nippon
Chemiphar Co., Ltd.) of JST and still studied actively.

Fig. 4 agonist and the structure of TAN-67 and KNT-127

Discovery of applicable disease of our synthesized antagonists

The creation of the abovementioned antagonists later led me to the
clarification of the precise pharmacological actions derived from the
opioid receptor types (the epoch-making discovery that the and
agonists, in particular, could separate drug dependence). I also found
out the strong antitussive effect of NTI and further subjected it to clinical
trial as an antitussive drug (TRK-851) free from drug dependence and
having more than 100 times higher activity than that of codeine. In
addition, I - found out that the 1 antagonist BNTX had the releasing
effect of the drug resistance of drug-resistant malaria and that the BNTX
derivatives suppressed not only the growth of malaria but also the those
of a wide variety of infectious protozoa. Interestingly, the mechanism of
this drug resistance release leads to inhibition of not only glutathione
itself but alsodrug efflux transporters, which may result in the inhibition
of CD44. From this fact, it is expected that the 1 antagonist will be the
great first step toward the creation of therapeutic drugs against drugresistant cancer.

Meaning of the achievements

Because of their dependence liability, opioids were treated as narcotics long
time, but by the research achievements by the applicants, their dependence
liability can be separated today. This findingdiscovery led to the new
discovery that opioids have not only an analgesic action but also antitussive,
antipruritic, antidepressant, anxiolytic, anti-pollakiuria, and antimalarial
effects, the suppressive effect of the angiogenesis of cancer cells, and many
other effects, and made a great contribution to the resolution of human
health problems. Furthermore, the creation of nalfurafine helped us to clarify
the mechanism of itching and find in collaboration with the University of
Pittsburgh the reason why people scratch when they feel itchy.