H3 receptor ligands: New imidazole H3-antagonists endowed with NO-donor properties

Article abstract of DOI:10.1016/S0014-827X(03)00023-5

Synthesis and pharmacological properties of a group of compounds obtained by coupling the H₃-antagonist SKF 91486 with the NO-donor 3-phenylfuroxan-4-yloxy and 3-benzenesulfonylfuroxan-4-yloxy moieties, as well as with the corresponding furazan analogues, devoid of NO-donating properties, are reported. All the products were tested for their H₃-antagonistic and H₂-agonistic properties on electrically-simulated guinea-pig ileum segments and guinea-pig papillary muscle, respectively. All the synthesised compounds displayed good H₃-antagonistic properties (pA₂ range 7.02-8.49) while behaving only as weak partial H₂-agonists. Derivative 28, the best NO-donor of the series, was able to trigger a dual NO-dependent muscle relaxation and H₃-antagonistic effect on guinea-pig illeum.

Full text of DOI:10.1016/S0014-827X(03)00023-5

Il Farmaco 58 (2003) 279Á283
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www.elsevier.com/locate/farmac
Short Communication
H3 receptor ligands: new imidazole H3-antagonists endowed with
NO-donor properties
Massimo Bertinaria
Dipartimento di Scienza e Tecnologia del Farmaco, Via P. Giuria, 9-10125 Turin, Italy
Accepted 4 July 2002
Abstract
Synthesis and pharmacological properties of a group of compounds obtained by coupling the H3-antagonist SKF 91486 with the
NO-donor 3-phenylfuroxan-4-yloxy and 3-benzenesulfonylfuroxan-4-yloxy moieties, as well as with the corresponding furazan
analogues, devoid of NO-donating properties, are reported. All the products were tested for their H3-antagonistic and H2-agonistic
properties on electrically-simulated guinea-pig ileum segments and guinea-pig papillary muscle, respectively. All the synthesised
compounds displayed good H3-antagonistic properties (pA2 range 7.02Á8.49) while behaving only as weak partial H2-agonists.
/
Derivative 28, the best NO-donor of the series, was able to trigger a dual NO-dependent muscle relaxation and H3-antagonistic
effect on guinea-pig illeum.
´
# 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: H3-antagonist; NO-donors; Furoxan derivatives
1. Introduction
Schizophrenia), memory enhancing and obesity control
[8]. Therapeutic uses of such antagonists in the periph-
ery have still to be established.
Nitric oxide (NO), a recently discovered endogenous
messenger displays in our body a variety of actions [9].
In the CNS it is released from neurons following
Histamine triggers its pharmacological actions by
three subtypes of receptors: the postsynaptic H1 and
H2 receptors and the presynaptic H3 receptor [1]. The H3
receptor was first identified in 1983 [2], since then much
has been written about the physiological role of this
receptor. The H3 receptor is principally located in the
central nervous system (CNS), where it acts as an
inhibitory autoreceptor in the central histaminergic
neuronal pathways [1]. In the brain, functional studies
have also provided evidence for inhibitory H3 receptors
on nerve terminals of noradrenergic, [3] serotoninergic,
[4] dopaminergic, [5] and peptidergic [6] neurons. The
H3 receptor has also been found to negatively modulate
transmitter release from peripheral cholinergic, adrener-
gic, and non adrenergic-non cholinergic (NANC) nerve
endings [7].
stimulation
of
excitatory
N-methyl-D-aspartate
(NMDA) receptors, it diffuses in the adjacent presynap-
tic nerve terminal and astrocytes where it activates the
soluble guanylate cyclase (sGC). This implies a number
of physiological roles including formation of memory
and control of food intake. Peripherically nitric oxide is
a key messenger in cardiovascular, nervous and immune
systems, where it elicits a wide range of physiological
and pathophysiological effects.
There is strong evidence that furoxan system (1,2,5-
oxadiazole, 2-oxide) is able to release nitric oxide (NO,
family name) under the action of thiol cofactors [10]. By
introducing appropriate substituents at the ring it is
possible to modulate rate and amount of NO-produc-
tion [11].
A number of therapeutic applications have been
proposed for selective H3 receptor antagonists, includ-
ing several CNS disorders (e.g. Alzheimer’s disease,
Attention Deficit Hyperactivity Disorder (ADHD),
Today there is a great interest in ‘hybrid’ drugs in
which NO-donor moieties are joined to appropriate
pharmacophoric groups. As a further development of
E-mail address: massimo.bertinaria@unito.it (M. Bertinaria).
´
0014-827X/03/$ - see front matter # 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
doi:10.1016/S0014-827X(03)00023-5

280
M. Bertinaria / Il Farmaco 58 (2003) 279Á283
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Fig. 1. General structure of H3-antagonists.
In order to obtain H3-antagonist-NO-donors we
chose SKF 91486 (Fig. 2) as the lead structure. The
choice of this pharmacophore should guarantee good
possibility of modulation without the loss of H3-
antagonistic properties [13].
SKF 91486 has been coupled, through appropriate
spacers, with 3-phenylfuroxan-4-yloxy and 3-benzensul-
fonylfuroxan-4-yloxy moieties. The structure of the
synthesised hybrids (24, 26, 28) is reported in Fig. 3.
As reference compounds we studied the corresponding
furazan models 23, 25, 27, since they are unable to
release NO.
Fig. 2. Lead structure.
our work in this direction we designed some H3-
antagonist-NO-donor hybrid molecules.
The general structure of an H3-antagonist is reported
in Fig. 1. Current H3-antagonists can be broadly
categorised as imidazole and non-imidazole compounds
depending on the employed heterocycle. The former
predominates, although progress with the latter has
recently been made [12].
2. Chemistry
Chain A is generally a short methylene chain with a
variable length from three to five carbon atoms.
According to our strategy, the synthesis of the final
products 23Á28, requires the preparation of intermedi-
/
Optimum antagonist activity is reached when nꢀ3.
/
ate N-benzoyl-O-phenylisourea (10) (Scheme 1). This
compound can be easily obtained by nucleophilic
displacement of the first phenoxy group present in N-
benzoyl-diphenylcarbonimidate (9), under the action of
3-(1-tritylimidazol-4-yl)propylamine (6). Preparation of
the amine 6 was achieved by two different approaches.
The first route implied the conversion of the alcohol 7
[14] into the phtalimido derivative 8, through a modified
Mitsunobu reaction and subsequent hydrolysis of this
intermediate in basic medium to afford 6 in good yield.
The second route started from trityl-protected iodoimi-
dazole 2 [15], which was successfully converted into the
corresponding aldehyde 3 by action of ethylmagnesium
bromide and DMF in CH2Cl2. The carbaldehyde 3 was
then converted to the a,b-unsaturated nitrile 4 by means
of a modified Wittig reaction; successive catalytic
hydrogenation (Pd/C) and mixed hydride reduction
The polar group can be different in its nature: guani-
dine, amidine, amine, ether, urea, thiourea, oxadiazole
and many other functionalities have been employed in
designing selective H3-antagonists. This part of the
molecule is thought to be responsible for the affinity
to H3 receptor, thus constituting the pharmacophoric
pattern. The lipophilic moiety connected to the phar-
macophore through chain B usually modulates the
potency of the antagonist.
with LiAlH4Á
/
AlCl3 in etherÁTHF (2/1) afforded the
/
expected aminoderivative 6. Owing to its instability, the
protected derivative 6 was reacted further with 9 to give
the above-mentioned O-phenylisourea (10).
Nucleophilic substitution of the phenoxy group in 10,
by the appropriate aminoalcohol provided the inter-
mediate 11 and 12. Under action of alcohols 11Á12 in
/
basic medium selective displacement of the 4-benzene-
sulfonyl group present on furoxan and furazan rings was
achieved to give the protected final products 17Á
(Scheme 2). Deprotection was performed by refluxing
with 5 N HCl to obtain 23Á26. Surprisingly, in the same
/
22
Fig. 3. Designed molecules.
/

M. Bertinaria / Il Farmaco 58 (2003) 279Á
/283
281
Scheme 1.
Table 1
Nitrite determination and pharmacological characterisation of derivatives 23Á
/28 and reference compound SKF 91486 and impromidine
a
b
c
Comp.
n
m
R
NO2ꢁ
%
H2-receptor activity pD29
/
SEM
H3-receptor antagonism pA29SEM
/
23
24
25
26
27
28
2
2
3
3
3
3
0
1
0
1
0
1
Ph
Ph
4.349
4.549
5.709
5.909
5.889
5.289
/
0.04
0.07
0.04
0.06
0.07
0.12
8.199
7.829
8.499
8.259
7.429
7.029
7.059
7.249
/
0.07
0.09
0.03
0.07
0.03
0.03
3.89
4.09
26.79
/
0.1
/
/
Ph
/
/
Ph
SO2Ph
SO2Ph
/
0.06
3.4
/
/
/
/
/
/
/
/0.05 (ꢂODQ)
/
SKF 91486
Histamine
Impromidine
4.499
6.159
7.499
/
0.07
0.02
0.04
/0.07
/
/
7.59 [18]
a
Compound 100 mM;
L
-Cys 5 mM.
Electrically stimulated guinea-pig papillary muscle. pD2ꢀ
Electrically stimulated guinea-pig ileum. pA2 values calculated according to Gaddum’s equation: pA2ꢀ
b
c
/
ꢁ
/
log EC50. Data are the mean of four to six experiments.
/
ꢁ
/
log[B]ꢂlog[CRꢁ1]. Data are the
/
/
mean of five to 11 experiments.

282
M. Bertinaria / Il Farmaco 58 (2003) 279Á283
/
Scheme 2.
Scheme 3.
acidic conditions, derivative 21Á
tatively with formation of benzenesulfonylmethyl chlo-
ride (29) as the main product (Scheme 3). Derivatives
/
22 decomposed quanti-
redox form released but nitrite production represents an
approximate index of total NO generation.
27Á28 were finally obtained with the use of 3 M p-
/
toluensulfonic acid at 95 8C (Scheme 2).
3. Pharmacology
The thiol-induced NO generation from synthesised
hybrids was evaluated by spectrophotometric nitrite
detection according to a previously reported procedure
[11]. The results expressed as NO2ꢁ % (mol/mol) are
reported in Table 1. It is noteworthy how this kind of
measure does not give information about the single NO-
The H3 receptor antagonism was evaluated by mea-
suring the ability of each compound (1 mM) to inhibit
the concentration dependent inhibitory effect of (R)-a-
methylhistamine on electrically evoked contractile re-
sponse of guinea-pig ileum preparation [16].

M. Bertinaria / Il Farmaco 58 (2003) 279Á
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283
[4] E. Schlicker, R. Betz, M. Gothert, Naunyn-Schmiederberg’s
¨
All the synthesised compounds were tested in a
stimulated guinea-pig papillary muscle model [17] to
determine their ability to activate H2 receptors.
Results expressed respectively as pA2 and pD2 values
are reported in Table 1.
Arch. Pharmacol. 337 (1988) 588Á
/590.
[5] E. Schlicker, K. Fink, M. Detzner, M. Gothert, J. Neural Transm.
¨
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839.
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All the synthesised compounds proved to be selective
H3-antagonists, with similar or greater potency than the
lead compound SKF 91486.
¨
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Derivative 28, when tested on guinea-pig ileum,
showed, together with the H3-antagonist properties, an
NO-dependent effect. This effect was observed as a
transient inhibition of the stimulated-tissue contraction
and was prevented by prior administration of ODQ (1
mM). This observation can prove the effective ‘hybrid
behaviour’ of this class of compounds, which represents
the first example of H3-antagonist-NO-donor molecules.
/
/
/
320.
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