Indoles and 1-(3-(benzyloxy)benzyl)piperazines: Reversible and selective monoamine oxidase B inhibitors identified by screening an in-house compound library.

The therapeutic indications for monoamine oxidases A and B (MAO-A and MAO-B) inhibitors that have emerged from biological studies on animal and cellular models of neurological and oncological diseases have focused drug discovery projects upon identifying reversible MAO inhibitors. Screening of our in-house academic compound library identified two hit compounds that inhibit MAO-B with IC50 values in micromolar range. Two series of indole (23 analogues) and 3-(benzyloxy)benzyl)piperazine (16 analogues) MAO-B inhibitors were derived from hits, and screened for their structure-activity relationships. Both series yielded low micromolar selective inhibitors of human MAO-B, namely indole 2 (IC50 = 12.63 ± 1.21 µM) and piperazine 39 (IC50 = 19.25 ± 4.89 µM), which is comparable to selective MAO-B inhibitor isatin (IC50 = 6.10 ± 2.81 µM), yet less potent in comparison to safinamide (IC50 = 0.029 ± 0.002 µM). Selective MAO-B inhibitors 2, 14, 38 and 39 exhibited favourable permeation of the blood-brain barrier and low cytotoxicity in the human neuroblastoma cell line SH-SY5Y.

Development of an in-vivo active reversible butyrylcholinesterase inhibitor.

Alzheimer's disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Similar to acetylcholinesterase, butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its enzymatic activity increases with the disease progression, thus classifying BChE as a viable therapeutic target in advanced AD. Potent, selective and reversible human BChE inhibitors were developed. The solved crystal structure of human BChE in complex with the most potent inhibitor reveals its binding mode and provides the molecular basis of its low nanomolar potency. Additionally, this compound is noncytotoxic and has neuroprotective properties. Furthermore, this inhibitor moderately crosses the blood-brain barrier and improves memory, cognitive functions and learning abilities of mice in a model of the cholinergic deficit that characterizes AD, without producing acute cholinergic adverse effects. Our study provides an advanced lead compound for developing drugs for alleviating symptoms caused by cholinergic hypofunction in advanced AD.

In vitro interactions between aged garlic extract and drugs used for the treatment of cardiovascular and diabetic patients.

BACKGROUND: Disease preventing effects gained by garlic consumption have been recognized since early period of history, making commercially available garlic supplements attractive to the general public. Possible pharmacokinetic interactions which could occur between applied drugs and aged garlic extract (AGE) are unknown. AIM: To test in vitro impact of some garlic phytochemicals on P-glycoprotein (Pgp), the most recognized efflux transporter, and the effect of AGE on passive membrane permeability, absorptive and secretory intestinal transporters. METHODS: Rat small intestine and Caco-2 cell monolayers, mounted in side-by-side diffusion chambers were used. RESULTS: Hydrophilic sulphur compounds increased Pgp mediated Rhodamine 123 (Rho123) efflux, whereas the lipophilic ones increased Pgp efflux through rat ileum but not through Caco-2 cell monolayers. Increased activities of secretory (Pgp, multidrug-resistance associated protein 2) and absorptive (monocarboxylate transporter 1, organic anion transporting polypeptide) transporters involved in drug absorption were observed in rat small intestine and Caco-2 cell monolayers in the presence of AGE. Transport of drugs mediated by breast cancer resistance protein and H(+)-oligopeptide transporter 1 was activated in rat intestine but inhibited through Caco-2 cells. Passive membrane permeability of tested compounds remained unaltered through rat small intestine, while significant changes were observed with Caco-2 cell monolayers. CONCLUSIONS: Due to the observed in vitro pharmacokinetic interactions between AGE and investigated cardiovascular, antidiabetic and antiviral drugs, in vivo absorption changes are possible, but the magnitude of change depends on the most profound process involved (influx, efflux, passive diffusion) in compounds permeability.

Aged garlic extract stimulates p-glycoprotein and multidrug resistance associated protein 2 mediated effluxes.

The growing concomitant consumption of drugs and herbal preparations such as garlic, and the numerous reports about the influence of herbal preparations on intestinal transport, led us to evaluate the influence of aged garlic extract on the transport function and electrophysiological parameters of the small intestinal mucosa. Aged garlic extract induced increase of the absolute value of the transepithelial potential difference and of the short-circuit current in both permeability models tested (rat jejunum, Caco-2 cell monolayers) without affecting transepithelial electrical resistance. It also caused a significant increase of the P-glycoprotein and multidrug resistance associated protein 2 mediated effluxes through rat jejunum of marker substrates Rhodamine 123 and 2,4-dinitrophenyl-S-glutathione, respectively. Rhodamine 123 efflux through the Caco-2 cell monolayers was not altered by aged garlic extract, whereas the efflux of 2,4-dinitrophenyl-S-glutathione increased significantly. So altered activity of the important transport proteins could significantly change the pharmacokinetic properties of conventional medicines taken concomitantly with aged garlic extract.