Role of hydrophobic substituents on the terminal nitrogen of histamine in receptor binding and agonist activity: Development of an orally active histamine type 3 receptor agonist and evaluation of its antistress activity in mice

Article abstract of DOI:10.1021/jm901890s

The terminal nitrogen atom of histamine was modified with lipophilic substituents to investigate the Structure-activity relationship of histamine type 3 receptor (H3R) agonists. The introduction of an alkylated benzene rings maintained or increased the H3

Full text of DOI:10.1021/jm901890s

3840 J. Med. Chem. 2010, 53, 3840–3844
DOI: 10.1021/jm901890s
Role of Hydrophobic Substituents on the Terminal Nitrogen of Histamine in Receptor Binding
and Agonist Activity: Development of an Orally Active Histamine Type 3 Receptor Agonist
and Evaluation of Its Antistress Activity in Mice
Makoto Ishikawa, Rie Shinei, Fumikazu Yokoyama, Miki Yamauchi, Masayo Oyama, Kunihiro Okuma,
Takako Nagayama, Kazuhiko Kato, Nobukazu Kakui, and Yasuo Sato*
Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan
Received January 5, 2010
The terminal nitrogen atom of histamine was modified with lipophilic substituents to investigate the
structure-activity relationship of histamine type 3 receptor (H3R) agonists. The introduction of an
alkylated benzene rings maintained or increased the H3R binding affinity. The most potent compound,
4-(2-(4-tert-butylphenylthio)ethyl)-1H-imidazole, possessed in vivo agonistic activity, decreasing brain
Nτ-methylhistamine levels in mice after oral administration. It also exhibited antistress activity in the
mouse resident-intruder test.
Introduction
The histamine type 3 receptor (H3Ra) was found in 1983 by
Arrang and colleagues.1 It acts not only as a presynaptic
autoreceptor, inhibiting the synthesis and release of histamine
in the brain, but also as a heteroreceptor modulating the
release of other neurotransmitters in both the central and
peripheral nervous systems.2-5 Human H3R cDNA was
identified in 1999 by Lovenberg and co-workers.6 The H3R
alsoexhibits constitutiveG-protein-coupledreceptor (GPCR)
activity.7,8 The H3R can signal independently of any agonist,
and careful classification of agonist, pure antagonist, and
Figure 1
inverse agonist is required in the study of H3R ligands. Many
selective H3R ligands have been identified, and some H3R
inverse agonists are in clinical trial for the treatment of
cognitive disorders, dementia, or narcolepsy.9-11 On the other
hand, therapeutic application of H3R agonists,12,13 has been
limited because potent H3R agonists, such as (R)-R-methyl-
histamine (1) and imetit (2), are highly hydrophilic and show
Figure 2
poor oral absorption or brain penatration14,15 (Figure 1).
Recently, more lipophilic H3R agonists, such as FUB 475 (3)16,
of ligands and may require a conformational change for signaling.
We considered that modifying the corresponding part of the
UCL 1470 (4)17, and N,N-dimethylimbutamine (5)18, have been
endogenous agonist histamine on the terminal nitrogen atom
might afford orally available H3R agonists and provide informa-
tion about the recognition of lipophilic structure by H3R. The aim
of our study is, therefore, to find novel, orally active H3R agonists
by modifying histamine with lipophilic substituents. The intro-
duction of an alkylated benzene ring at the terminal nitrogen atom
recovered or increased the agonistic activity toward human H3R.
The most potent compound showed in vivo agonistic activity
in mice, modulating the brain Nτ-methylhistamine level, and
also showed antistress activity in the mouse resident-intruder
test.
Chemistry. 4-(2-Bromoethyl)imidazole (6) was prepared
according to Bloemhoff and Kerling.19 Alkyl or aryl amines
were introduced by heating the appropriate derivative with 6
in DMF. To obtain the thioether derivative, 4-tert-butylthio-
phenol was treated with NaH at 60 °C in DMF, then
reported. All of them have a 4-alkylated imidazole ring and a
terminal lipophilic moiety with or without a nitrogen atom.
Compounds 3 and 4 showed H3R agonistic activity in vivo
following oral administration. However, the structure-activity
relationship of H3R agonists is still poorly understood. Modifica-
tions tend to change the agonistic activity to antagonistic or
inverse agonistic activity, even if the binding affinity is maintained.
It appears that the H3R strictly recognizes the hydrophobic part
*To whom correspondence should be addressed. Phone: þ81-3-3273-
3086. Fax: þ81-3-3273-3380. E-mail: yasuo_sato@meiji.co.jp.
a Abbreviations: H3R, histamine type 3 receptor; cDNA, cloned
DNA; GPCR, G-protein-coupled receptor; DMF, N,N-dimethylform-
amide; NaH, sodium hydride; [35S]GTPγ[S], [35S]guanosine 50-[γ-thio]-
triphosphate; CHO cell, Chinese hamster ovary cell; CYP, cytochrome
P450; mRNA, mRNA; HPA, hypothalamic-pituitary-adrenal; CRF,
corticotropin releasing factor.
r
pubs.acs.org/jmc
Published on Web 04/12/2010
2010 American Chemical Society

Brief Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9 3841
Table 1. In Vitro Binding and Functional Assay in Human H3R
a Each result represents the mean ( SEM (n = 3). b Percent ratio to the response obtained from 1. c Not active.
4-(2-bromoethyl)imidazole was added to the reaction mix-
ture, and further heating for 16 h afforded the coupling
compound 7h (Figure 2).
Pharmacology. In Vitro Human H3R Studies. The affinity
(pKi) values and the functional activities were determined
using CHO cells stably expressing the human H3R.20,21 The
procedures are described in Supporting Information.
In Vivo Mouse Studies. The Nτ-methylhistamine level in the
brain of mice was measured following oral administration of
the test compounds.22,23 The mouse resident-intruder test
was performed according to Sanchez and Hyttel.24 The
procedures are described in Supporting Information.
Results and Discussion
The results of examination of H3R binding and agonist
activity of the synthesized compounds are presented in Table 1.
Compared with the standard compounds 1 and 2, introduction
of a cyclohexane ring resulted in loss of agonistic activity (7a).
Intriguingly, the change of a cyclohexane ring (7a) to a
benzene ring (7b) clearly improved the binding affinity

3842 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9
Ishikawa et al.
Table 2. Nτ-Methylhistamine Level (ng/g Tissue) in the Brain of Mice
Table 4. Duration of Attacks (s) in Mouse Resident-Intruder Testa
Following Oral Administrationa
compd
control
3 mg/kg
7.5 mg/kg
30 mg/kg
compd
control
1 mg/kg
5 mg/kg
30 mg/kg
fluvoxamine
7h
54.5 ( 6.7
54.5 ( 6.7
30.7 ( 6.0
19.9 ( 3.5b
98 ( 11b
42.9 ( 9.5
16.3 ( 6.8b
2
7h
315 ( 20
315 ( 20
239 ( 19
298 ( 38
133 ( 14
92 ( 7b
96 ( 8b
a Each result represents the mean ( SEM of eight animals. b p < 0.01
vs vehicle control. The test compound was administered po.
a Each result represents the mean ( SEM of five animals. b p < 0.01 vs
vehicle control.
activitythrough blocking excessiverelease of corticosterone in
rats.28 Overactivation of the hypothalamic-pituitary-adrenal
(HPA) axis, such as elevationof plasma cortisol, was observed
in patients with major depression, and this change was
normalized in response to therapy.29 Corticotropin releasing
factor (CRF) is an upstream factor in the HPA axis, and CRF
type I receptor antagonists have been studied as novel anti-
depressant drug candidates.30,31 It was reported that central
administration of histamine increased CRF mRNA in rats.32
H3R agonists might show antistress activity by the functional
modulation of CRF neurons via inhibition of histamine
release in the central nervous system and through control of
the HPA axis.
In regards to the profile of activity toward human cloned
histamine receptor subtypes, 7h showed good selectivity over
H1 and H2 receptors (Ki>1 μM) but displayed similar binding
affinity for the H4 receptor (Ki = 1.1 nM, Ki(H4)/Ki(H3) =
6.5). Some conventional H3R agonists, such as 1 and 2,
exhibit binding affinity for both H3 and H4 receptors, pre-
sumably because the newly identified H4 receptor has a high
sequence homology to H3R (54% in the transmembrane
domains in humans).33 Because the H4 receptor is not ex-
pressed in the brains of rodents,34 the result obtained with 7h
in the mouse resident-intruder test should not be related to H4
receptor activity. One of the cyclopropane-based conforma-
tionally restricted histamine analogues has been reported to
show increased H3R selectivity.35 Recently 4-benzyl-1H-imi-
dazoles were also reported as novel H3R agonists.36 We have
set out to design and synthesize further H3R agonists, aiming
to improve the selectivity between H3 and H4 receptors by
introducing conformational restrictions. Compound 7h showed
high selectivity against other aminergic receptors (Ki>1 μM:
Table 3. In Vitro and in Vivo Rat Pharmacokinetic Parameters for 7h
in vivob
(2 mg/kg, iv)
in vivob
(5 mg/kg, po)
in vitroa
S9 metabolic
activity
(pmol/min/mg
protein)
Cltot
(L/h/kg) (L/kg) (h) (mg h/mL) (%)
Vdss t1/2 AUC0-inf BA brain/plasma
ratioc
3
0.99
13.0 ( 0.9
2.8
3.4 1.0
53.5
6.0
a Mean ( SEM, n = 3. b n = 2. c Ratio at 1 h after administration.
(Ki = 1600-56 nM). 4-Methylation of the aromatic ring of 7b
increased the H3R agonist activity (7c, EC50 = 88 nM). A 3,4-
dimethylbenzene ring resulted in a moderate improvement of
H3R affinity (7d). Optimization of the para substitution of the
aromatic ring for agonistic activity led to the tert-butyl moiety;
the 4-tert-butyl compound exhibited excellent activity (7e, Ki =
0.89 nM, EC50 = 1.6 nM, ia = 70%). The 3-tert-butyl com-
pound (7f) was inferior to the 4-tert-butyl derivative. The
introduction of a bulkier alkyl group, a cyclohexane ring,
resulted in loss of agonistic activity, even though high affinity
was retained (7g, Ki = 4.1 nM). The 4-tert-butyl phenyl
thioether compound 7h showed the most potent H3R agonist
activity (Ki = 0.17 nM, EC50 = 0.75 nM, ia = 77%) among
the compounds examined. The 4-trifluoromethyl (7i) and
4-methoxy (7j) compounds had higher potency but similar
efficacy in the functional assay compared with the 4-methyl
derivative 7c. These results indicate that the combination of a
benzene ring and an alkyl substituent of appropriate bulkiness
is important for agonist activity of terminally nitrogen-modi-
fied histamine.
The most potent compound 7h was further studied in vivo.
Inthe Nτ-methylhistamineformationassay in mousebrain, 7h
induced a significant reduction of Nτ-methylhistamine level
following oral administration. The response at 5 and 30mg/kg
was similar to that in the case of the full H3R agonist 2
(Table 2). Compound 7h is more lipophilic than 2 and there-
fore may cross the blood-brain barrier more effectively. How-
ever, the dose-response relationship in terms of Nτ-methyl-
histamine level was almost the same for the two compounds,
and their binding affinities were also similar. In mice, the
aromatic ring and thioether structure of 7h could cause this
compound to be metabolized faster than 2, which has an
isothiourea structure.15 7h showed acceptable profiles in rat
pharmacokinetic tests (Table 3).
adrenergic R1, β1, β2; muscarinic M1, M3; serotonergic 5-HT1A
,
5-HT2A, 5-HT3; dopaminergic D1, D2, D3). As for the lead
compound for drug development, 7h exhibited an unfavorable
profile in the inhibition of CYP enzymes (CYP1A2, CYP2C19,
CYP2D6, and CYP3A4; IC50 values 680, 8.5, 680, 470 nM,
respectively). This also should be considered in further com-
pound design.37
Conclusion
Chemical modification of the terminal amine of histamine
afforded novelH3R agonists containinganaromatic ring with
a hydrophobic substituent on the para and/or meta position.
The introduction of a cyclohexyl group (7g) resulted in loss of
agonistic activity despite retention of affinity for H3R. The
most potent compound 7h showed H3R agonistic activity and
antistress activity in mice in vivo.
On the basis of our structure-activity data and reported
findings,36 we hypothesize that two binding sites, a terminal
heteroatom recognition site and a hydrophobic pocket, are
involved in the binding of agonists to H3R, and they are
located in close proximity. Compounds such as 7e and 7h
could interact with both sites. Further studies with conforma-
tionally restricted H3R ligands might clarify the spatial
relationship of these sites.
H3R agonists are expected to be candidate drugs to im-
prove migraine, nociception, and sleep disorder.25 We are
interested in the antistress effect of H3R agonists, because in
some animal stress models, an increase of brain histamine
release has been recognized.26 We have already found that 1
significantly reduced isolation-induced vocalizations in guinea
pig pups and isolation-induced aggressive behavior in mice in
the resident-intruder test.27 In the mouse resident-intruder
test, treatment with 7h at 30 mg/kg also significantly reduced
the duration of attacks on the intruder (Table 4).
In a study of selective serotonin reuptake inhibitors, we had
obtained evidence that fluvoxamine might exhibit therapeutic

Brief Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 9 3843
Experimental Section
mouse brain, mouse resident-intruder test, and pharmaco-
kinetic tests in rats. This material is available free of charge
via the Internet at http://pubs.acs.org.
1H and 13C NMR spectra were obtained on JEOL LA-400
FT-NMR spectrometers. Mass spectra were recorded on Hitachi
M-80B and JEOL JMS-700 instruments. Elemental analysis data
were obtained on a VarioEL (Elementar), and purity over 95%
was confirmed for all synthesized compounds. Histamine, 1, and
2 were commercial products.
Profiling of binding affinity for receptors other than H3R was
done by MDS Pharma Services. All biological results are ex-
pressed as mean ( SEM Statistical analysis was performed with
the SAS statistical package (SAS Institute Japan, Tokyo, Japan).
The statistical significance of differences among multiple groups
was tested by one-way analysis of variance followed by Dunnett’s
multiplecomparison test. A two-tailed Student’st testwas used to
evaluate differences between two experimental groups. Differ-
ences were considered significant at p<0.05. Animal care was
performed according to the protocols reviewed by the Ethical
Committee for Animal Experiment in Meiji Seika Pharmaceuti-
cal Research Center.
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