Abstract
The association of the isoxazole and dihydropyridine (DHP) ring systems fused at the 4'-isoxazolyl- to the 4-position of the DHP has produced a combination scaffold, the isoxazolyl-DHPs (IDHPs) with unique conformational characteristics. The IDHPs are useful in probing biological activity, as exemplified by our efforts in the fields of voltage gated calcium channel (VGCC) antagonists and inhibitors of the multi-drug resistance (MDR) transporter. A strategically placed methyl group produced a signifcant change at the VGCC, with (R)-(+)-1-phenyl-prop-2-yl (3.7 nM) > phenethyl (22.9 nM) > (S)-(-)-1-phenyl-prop-2-yl (210 nM), a eudismic ratio of 56.7. Branching at the C-5 of the isoxazole produced a 25% increase in MDR binding, and replacing the DHP C-3 ester with a functionalized amide also gave a dramatic increase in binding affinity. Opportunities for combined scaffolds – including examples containing IDHPs – are waiting to be discovered: because new biology is driven by new chemistry.
Acknowledgement
This work would not have been possible without the hard work of a dedicated group of students in my group over the years. Worthy of note is the fact that the first IDHP prepared by Dave Quincy as an undergraduate in the summer of 1982, was found many years later to be a robust inhibitor of MDR-1. MDR-1 data was generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program (NIMH PDSP), Contract # HHSN-2712–0080–0025-C (NIMH PDSP). The NIMH PDSP is directed by BL Roth at the University of North Carolina at Chapel Hill (NC. USA) and Project Officer J Driscol l at NIMH (MD, USA).
Financial & competing interests disclosure
The authors are grateful for support from the University of Idaho Research Council, the Research Corporation, the National Institutes of Health NIGMS R15 GM42029 and the annual summer stipend support from the Malcolm and Carol Renfrew Endowment. At the University of Montana, support has been provided by the Center for Structural and Functional Neuroscience NINDS P20RR015583 (NRN) and Montana NSF EPSCOR Grant ESP-0701906 (SAS). We thank the Skaggs Scholar Program for current support. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.