7 research outputs found
Diet of the chola guitarfish, Rhinobatos percellens (Rhinobatidae), in the Paranaguá Estuarine complex
The role of dietary fatty acid intake in inflammatory gene expression: a critical review
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-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=6nM, EC50=19nM, 176-fold selectivity over 5-HT1AR) and 1e
(5-methoxy analogue, Ki 5-HT7=30nM, EC50=60nM) 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. (5mg/kg) administration in mice. The compound was found active
in novel object recognition test in mice, at 0.5, 1 and 5mg/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