Abstract
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-HT7 receptor together with agonist function. The chosen lead compounds 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-1H-indole (AGH-107, 1o, Ki 5-HT7 = 6 nM, EC50 = 19 nM, 176-fold selectivity over 5-HT1AR) and 1e (5-methoxy analogue, Ki 5-HT7 = 30 nM, EC50 = 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 (Cmax = 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-HT7R 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-HT1AR selectivity.
Highlights
Within the serotonergic system, 5-HT7, the last identified serotonin receptor, is one of the most valuable drug targets[1]
We believed that the close serotonin analogues 1a (AGH-38) and 1b (AGH-39) (Figs 1 and 2), which can be concisely prepared via van Leusen tosylmethylisocyanide (TosMIC) imidazole synthesis[43, 44], would exhibit activity at some serotonin receptors
Most of the indole-3-carboxaldehydes used were synthesized by the Vilsmeier-Haack formylation of the appropriate indoles
Summary
5-HT7, the last identified serotonin receptor, is one of the most valuable drug targets[1]. There are several 5-HT7R agonists available to serve as molecular probes These include small, low-weight molecules, e.g. AS-1926, RA-77, 5-carboxyamidotryptamine (5-CT), 5-methoxytryptamine, 8-OH-DPAT27, and lysergic acid derivatives[28] and long-chain diphenylpiperazines (LP-12, LP-44, LP-211) developed by Leopoldo et al.[29,30,31]. None of these compounds qualify as perfect radioligand candidates, mainly due to their poor selectivity. Been used in numerous in vivo experiments which led to the characterization of the receptor It was found, that 5-HT7 agonists can enhance long-term memory formation. We believed that the close serotonin analogues 1a (AGH-38) and 1b (AGH-39) (Figs 1 and 2), which can be concisely prepared via van Leusen tosylmethylisocyanide (TosMIC) imidazole synthesis[43, 44], would exhibit activity at some serotonin receptors
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