potential application of this type of compounds as imaging
ligands was simultaneously investigated.
dipolar cycloaddition of azides and acetylenes, 1,4-
disubstituted 1,2,3-triazoles were formed under copper(I)
catalysis (Scheme 2).8
The project was realized by coupling ferrocene derivatives
to the hH3R-targeting domain in the western molecule part
using different synthetic approaches. Therefore, the ap-
plicability of click chemistry in the design of hH3R ligands
was tested. All final compounds were characterized with
regard to hH3R binding potencies and selectivity over the
closely related hH1R and hH4R subtypes.
Scheme 2. Synthesis of Compounds 5-8
Synthesis of precursors P1 and P3-P5 as well as
compound 4 was performed as described before. Briefly,
ω-piperidinylalkanoles were chlorinated and subsequently
coupled to para-substituted phenols. The high-yielding
Williamson-like reactions completed by a Finkelstein
exchange were used to generate a small selection of
precursors.5 Alkyl- and benzyl-substituted chlorides
P3-P5 were converted into the corresponding azides
P6-P8 using water as solvent. Microwave irradiation was
used as an additional means to obtain P8.6 Precursor
compound P2 was comercially available.
Scheme 1. Synthesis of Compounds 1-4
The hH3R affinities (i.e., receptor binding strenghts) of
all final compounds 1-8 were determined by measuring
the displacement of [125I]iodoproxyfan from hH3R stably
expressed in HEK-293 cells.9 Compounds with pKi values
>7.0 (1-3, 7, 8) were investigated with regard to their
hH1R and hH4R affinities as described before (Table 1).
The hH3R inverse agonist efficacy was confirmed in a
[35S]GTPγS binding assay with compounds 1 and 8.10 The
potencies in the CNS evoked by compounds with hH3R
affinities in the picomolar concentration range (1, 2) was
determined in vivo by measuring histamine turnover in a
radioimmunoassay after peroral (p.o.) application.11
Compounds 1 and 2 belong to the class of diamine-based
ligands. A second basic moiety usually boosts hH3R
potency due to a second ionic interaction between receptor
protein and ligand.12 As expected, both amines strongly
interact with the binding pocket showing affinities in the
subnanomolar concentration range. However, this class
Following the typical hH3R affine structural blueprint,
the receptor-targeting domain, 1-(3-phenoxypropyl)pip-
eridine, was obtained. Different substituents in the para-
position of the phenyl ether element allowed the connec-
tion to a variety of residues that have a major influence
on physicochemical properties of the compounds. Ligands
1-3 were prepared via reductive amination and N,N′-
carbonyldiimidazole-provided amidation, respectively
(Scheme 1).7 Compounds 5-8 were prepared via the
efficient click-chemistry approach. In a Huisgen 1,3-
(7) (a) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff,
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271, 452. (b) Ligneau, X.; Perrin, D.; Landais, L.; Camelin, J. C.; Calmels,
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(12) (a) Axe, F. U.; Bembenek, S. D.; Szalma, S. J. Mol. Graph. Model.
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D.; Seifert, R.; Stark, H.; Holtje, H. D.; Sippl, W. J. Comput. Aided Mol.
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