Multitarget-Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H3 R Antagonism for Neurodegenerative Diseases.

The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg-1 i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.

From medicinal plant extracts to defined chemical compounds targeting the histamine H4 receptor: Curcuma longa in the treatment of inflammation.

OBJECTIVES: The aim was to evaluate the activity of seven medicinal, anti-inflammatory plants at the hH4R with focus on defined chemical compounds from Curcuma longa. MATERIALS: Activities were analyzed with membrane preparations from Sf9 cells, transiently expressing the hH4R, Gαi2 and Gß1γ2 subunits. METHODS: From the methanolic extract of C. longa curcumin (1), demethoxycurcumin (2) and bis(4-hydroxy-cinnamoyl)methane (3) were isolated, purified with HPLC (elution-time 10.20, 9.66, 9.20 min, respectively) and together with six additional extracts, were characterized via radioligand binding studies at the hH4R. RESULTS: Compounds from C. longa were the most potent ligands at the hH4R. They exhibited estimated K i values of 4.26-6.26 µM (1.57-2.31 µg/mL) (1); 6.66--8.97 µM (2.26-3.04 µg/mL) (2) and 10.24-14.57 µM (3.16-4.49 µg/mL) (3) (95% CI). The estimated K i value of the crude extract of curcuma was 0.50-0.81 µg/mL. Fractionated curcumin and the crude extract surpassed the effect of pure curcumin with a K i value of 5.54 µM or 2.04 µg/mL [95% CI (4.47-6.86 µM), (1.65-2.53 µg/mL)]. CONCLUSION: Within this study, defined compounds of C. longa were recognized as potential ligands and reasonable lead structures at the hH4R. The mode of anti-inflammatory action of curcumin was further elucidated and the role of extracts in traditional phytomedicine was strengthened.

The Synthesis of 1,3,5-triazine Derivatives and JNJ7777120 Analogues with Histamine H4 Receptor Affinity and Their Interaction with PTEN Promoter.

The involvement of histamine and H4 receptor (H4 R) in cancer has been investigated recently using the H4 R agonists and antagonists. The scope of the research project was synthesis and exploration of the consequences of a group of compounds with histamine H4 receptor (H4 R) affinity on the promoter of PTEN gene encoding the antitumor PTEN protein. The series of novel compounds based either on H4 R antagonists JNJ7777120 structure or 1,3,5-triazine scaffold were synthesized, evaluated for histamine H4 R affinity and used in this study. Compounds 5 and 7 belonging to the group of JNJ7777120 analogues showed the highest interaction with the promoter of PTEN gene and weak affinity against H4 R with Ki value >100 µm. These compounds showed no significant effect on neuroblastoma IMR-32 cells viability indicating no correlation between PTEN gene promoter affinity and antitumor activity. Compound 6, another JNJ7777120 analogue, showed the highest effect on IMR-32 viability with calculated IC50 = 23.27 µm. The 1,3,5-triazine derivatives exhibited generally low or medium interaction with PTEN gene promoter. However, the 1,3,5-triazine derivative 11 with the para-bromo substituent showed the highest affinity against H4 R with Ki value of 520 nm and may be considered as a new lead structure.