Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol
A series of 5-aryl-1-alkylimidazole derivatives was synthesized using the van Leusen multicomponent reaction. The chemotype is the first example of low-basicity scaffolds exhibiting high affinity for 5-HT 7 receptor together with agonist function. The chosen lead compounds 3-(1-ethyl-1 H -imidazol-5...
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Published in | Scientific reports Vol. 7; no. 1; p. 1444 |
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Main Authors | , , , , , , , , , , , , , , |
Format | Journal Article Web Resource |
Language | English |
Published |
London
Nature Publishing Group UK
04.05.2017
Nature Publishing Group Nature Portfolio |
Subjects | |
Online Access | Get full text |
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Summary: | A series of 5-aryl-1-alkylimidazole derivatives was synthesized using the van Leusen multicomponent reaction. The chemotype is the first example of low-basicity scaffolds exhibiting high affinity for 5-HT
7
receptor together with agonist function. The chosen lead compounds 3-(1-ethyl-1
H
-imidazol-5-yl)-5-iodo-1
H
-indole (AGH-107,
1o
,
K
i 5-HT7
= 6 nM, EC
50
= 19 nM, 176-fold selectivity over 5-HT
1A
R) and
1e
(5-methoxy analogue,
K
i 5-HT7
= 30 nM, EC
50
= 60 nM) exhibited high selectivity over related CNS targets, high metabolic stability and low toxicity in HEK-293 and HepG2 cell cultures. A rapid absorption to the blood, high blood-brain barrier permeation and a very high peak concentration in the brain (C
max
= 2723 ng/g) were found for
1o
after
i
.
p
. (5 mg/kg) administration in mice. The compound was found active in novel object recognition test in mice, at 0.5, 1 and 5 mg/kg. Docking to 5-HT
7
R homology models indicated a plausible binding mode which explain the unusually high selectivity over the related CNS targets. Halogen bond formation between the most potent derivatives and the receptor is consistent with both the docking results and SAR. 5-Chlorine, bromine and iodine substitution resulted in a 13, 27 and 89-fold increase in binding affinities, respectively, and in enhanced 5-HT
1A
R selectivity. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 scopus-id:2-s2.0-85018379921 |
ISSN: | 2045-2322 2045-2322 |
DOI: | 10.1038/s41598-017-00822-4 |