4-Isoxazolyl-1,4-dihydropyridines exhibit binding at the multidrug-resistance transporter

Abstract

The 4-Isoxazolyl-dihydropyridines (IDHPs) exhibit inhibition of the multidrug-resistance transporter (MDR-1), and exhibit an SAR distinct from their activity at voltage gated calcium channels (VGCC). Among the four most active IDHPs, three were branched at C-5 of the isoxazole, including the most active analog, 1k.

Fluorescent probes of the isoxazole–dihydropyridine scaffold: MDR-1 binding and homology model

“…5b,14–16,24 The danzyl probes, most notably 3c , in addition to the expected set of signals for the isoxazolyl-DHP, also exhibited a second set of signals with pronounced magnetic anisotropy in typical organic solvents (i.e., CDCl 3 ), and of equal intensity. Nuclear Overhauser spectroscopy evidenced interactions between the DHP C(2) and C(6) methyls with the Isoxazolyl C(3) phenyl, and the Isoxazolyl C(3) phenyl with the dimethyl amino groups of the dansyl moiety, indicative of a folded conformation.…”

“…21,22 This represents a significant increase in MDR-1 binding compared to IDHP- 1 , which exhibited a value of 48.9% in the PDSP assay. 23,24 …”

“…Recently, we found that IDHPs exemplified by structure 1 are in fact robust ligands of MDR-1, 24 in studies conducted in collaboration with the Psychoactive Drug Screening Program (PDSP), and exhibit an SAR distinct from their activity at the VGCC. In the present study we wished to test the hypothesis as to whether bivalent IDHPs would have enhanced activity at MDR-1.…”

Dimeric isoxazolyl-1,4-dihydropyridines have enhanced binding at the multi-drug resistance transporter

“…In our initial study, we found that branching at the C(5) of the isoxazole gave rise to three of the four most efficacious IDHPs at MDR-1. 11 In a follow-up study, attachment of a fluorophore also enhanced activity. This suggested additional binding opportunities in proximity to the putative nucleotide binding domain (NBD) of IDHPs ( vide infra ).…”

“…Dihydropyridines (DHPs) have been under intense study for many years for their ability to inhibit the multidrug transporter. 9,10 More recently we have reported that 4-isoxazolyl-1,4-dihydropyridines (IDHPs) have significant binding at this target, 11–13 and a unique structure activity relationship (SAR) which diverges from their voltage gated calcium channel (VGCC) activity. In our initial study, we found that branching at the C(5) of the isoxazole gave rise to three of the four most efficacious IDHPs at MDR-1.…”