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The enzyme butyrylcholinesterase (BChE) and the human cannabinoid receptor 2 (hCB2R) represent promising targets for pharmacotherapy in the later stages of Alzheimer's disease. We merged pharmacophores for both targets into small benzimidazole-based molecules, investigated SARs, and identified several dual-acting ligands with a balanced affinity/inhibitory activity and an excellent selectivity over both hCB1R and hAChE. A homology model for the hCB2R was developed based on the hCB1R crystal structure and used for molecular dynamics studies to investigate binding modes. In vitro studies proved hCB2R agonism. Unwanted μ-opioid receptor affinity could be designed out. One well-balanced dual-acting and selective hBChE inhibitor/hCB2R agonist showed superior in vivo activity over the lead CB2 agonist with regards to cognition improvement. The data shows the possibility to combine a small molecule with selective and balanced GPCR-activity/enzyme inhibition and in vivo activity for the therapy of AD and may help to rationalize the development of other dual-acting ligands. [ABSTRACT FROM AUTHOR]

A seriesof ruthenium(II) arene complexes with the 4-(biphenyl-4-carbonyl)-3-methyl-1-phenyl-5-pyrazolonateligand, and related 1,3,5-triaza-7-phosphaadamantane (PTA) derivatives,has been synthesized. The compounds have been characterized by NMRand IR spectroscopy, ESI mass spectrometry, elemental analysis, andX-ray crystallography. Antiproliferative activity in four human cancercell lines was determined by MTT assay, yielding dose- and cancercell line-dependent IC50values of 9–34 μMfor three hexamethylbenzene–ruthenium complexes, whereas theother metal complexes were much less active. Apoptosis was the mechanisminvolved in the anticancer activity of such compounds. In fact, thehexamethylbenzene–ruthenium complexes activated caspase activity,with consequent DNA fragmentation, accumulation of pro-apoptotic proteins(p27, p53, p89 PARP fragments), and the concomitant down-regulationof antiapoptotic protein Bcl-2. Biosensor-based binding studies indicatedthat the ancillary ligands were critical in determining the DNA bindingaffinities, and competition binding experiments further characterizedthe nature of the interaction. [ABSTRACT FROM AUTHOR]

5-HT1Areceptor and α1-adrenoreceptor(α1-AR) binding sites recognized by the 1,4-dioxanes 2–4display reversed stereochemical requirements.(S)-2proved to be a potent 5-HT1Areceptor agonist highly selective over α1-AR subtypes. Chirality influenced the anticancer activity of 3and 4in human prostate cancer cells (PC-3):(R)-4, eutomer at the α1d-AR subtype, was the most potent. The decreased effect of 4and (R)-4in α1d-ARsilenced PC-3 cells confirmed that their anticancer activity was α1d-AR-dependent. [ABSTRACT FROM AUTHOR]