Perspectives of P-Glycoprotein Modulating Agents in Oncology and Neurodegenerative Diseases: Pharmaceutical, Biological, and Diagnostic Potentials

From mixed sigma-2 receptor/P-glycoprotein targeting agents to selective P-glycoprotein modulators: Small structural changes address the mechanism of interaction at the efflux pump

“…For these reasons, P-gp modulators acting as Pgp substrates (i.e. actively transported by the pump out of the cell), or as P-gp inhibitors (able to bind the pump without being effluxed) should allow chemotherapeutic agents to entering the cells and exert their anticancer properties [4]. Scientific research has been very active towards this direction with three generations of P-gp inhibitors already developed for this purpose.…”

Multidrug resistance (MDR) reversers: High activity and efficacy in a series of asymmetrical N,N-bis(alkanol)amine aryl esters

“…Nevertheless, the search for new, safer, more potent and efficacious multidrug transporter modulators is still of interest, considering that such modulators seem to be useful for different purposes. In fact, P-gp has been recently considered an interesting target for CNS pathologies on the basis that it is an integral part of BBB [19,20]. It has been proposed that in Alzheimer's disease, the extrusion through the BBB membrane of toxic Ab amyloid, often because of age-related reduction of P-gp, is impaired and that positive modulation of the transporter, for instance through P-gp enhancers, would be beneficial in preventing the disease [21,22].…”

Biomarkers for the early diagnosis of Alzheimer’s disease: The challenge of XXI century

“…P-glycoprotein (P-gp) is an ATPase belonging to the ATP Binding Cassette (ABC) transporters family, transmembrane proteins able to efflux xenobiotics out of cells using the energy by ATP hydrolysis [49]. This protein is highly expressed at the luminal surface of brain capillary endothelium and is the major component of BBB; because of this strategic localization, P-gp exerts a protecttive function in the BBB.…”

“…These findings support the hypothesis that a P-gp dysfunction in the BBB could play a pivotal role in AD onset. Moreover, it was demonstrated that Aβ is a P-gp substrate [49]. Therefore, P-gp ligands could be used as PET tracers to detect P-gp activity and expression allowing an early diagnosis of AD.…”

“…P-gp ligands can be classified as: substrates, inhibitors and modulators. Substrates are actively transported by P-gp in an ATP-dependent manner and therefore their concentration is higher outside the cell with respect to the cytosol (Figure 8(a)) [49]. Modulators are able to alter substrate binding in a non competitive manner by interacting with P-gp within a distinct site from that of the substrate (Figure 8(b)).…”