Dataset Information

Improved Cav2.2 Channel Inhibitors through a gem-Dimethylsulfone Bioisostere Replacement of a Labile Sulfonamide.

ABSTRACT: We report the investigation of sulfonamide-derived Cav2.2 inhibitors to address drug-metabolism liabilities with this lead class of analgesics. Modification of the benzamide substituent provided improvements in both potency and selectivity. However, we discovered that formation of the persistent 3-(trifluoromethyl)benzenesulfonamide metabolite was an endemic problem in the sulfonamide series and that the replacement of the center aminopiperidine scaffold failed to prevent this metabolic pathway. This issue was eventually addressed by application of a bioisostere strategy. The new gem-dimethyl sulfone series retained Cav2.2 potency without the liability of the circulating sulfonamide metabolite.

SUBMITTER: Shao PP

PROVIDER: S-EPMC4027232 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Improved Cav2.2 Channel Inhibitors through a gem-Dimethylsulfone Bioisostere Replacement of a Labile Sulfonamide.

Shao Pengcheng P PP Ye Feng F Chakravarty Prasun K PK Herrington James B JB Dai Ge G Bugianesi Randal M RM Haedo Rodolfo J RJ Swensen Andrew M AM Warren Vivien A VA Smith McHardy M MM Garcia Maria L ML McManus Owen B OB Lyons Kathryn A KA Li Xiaohua X Green Mitchell M Jochnowitz Nina N McGowan Erin E Mistry Shruti S Sun Shu-Yu SY Abbadie Catherine C Kaczorowski Gregory J GJ Duffy Joseph L JL

ACS medicinal chemistry letters 20130908 11

We report the investigation of sulfonamide-derived Cav2.2 inhibitors to address drug-metabolism liabilities with this lead class of analgesics. Modification of the benzamide substituent provided improvements in both potency and selectivity. However, we discovered that formation of the persistent 3-(trifluoromethyl)benzenesulfonamide metabolite was an endemic problem in the sulfonamide series and that the replacement of the center aminopiperidine scaffold failed to prevent this metabolic pathway. ...[more]

PMID: 24900606

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Project description:We have examined the regulation of mutually exclusive Cav2.2 exon 37a and b variants by the mouse ?-opioid receptor (mMOR) C-terminal splice variants 1, 1C and 1O in tsA-201 cells. Electrophysiological analyses revealed that both channel isoforms exhibit DAMGO-induced voltage-dependent (G??-mediated) inhibition and its recovery by voltage pre-pulses, as well as a voltage-independent component. However, the two channel isoforms differ in their relative extent of voltage-dependent and independent inhibition, with Cav2.2-37b showing significantly more voltage-dependent inhibition upon activation of the three mMOR receptors studied. In addition, coexpression of either mMOR1 or mMOR1C results in an agonist-independent reduction in the peak current density of Cav2.2-37a channels, whereas the peak current density of Cav2.2-37b does not appear to be affected. Interestingly, this decrease is not due to an effect on channel expression at the plasma membrane, as demonstrated by biotinylation experiments. We further examined the mechanism underlying the agonist-independent modulation of Cav2.2-37a by mMOR1C. Incubation of cells with pertussis toxin did not affect the mMOR1C mediated inhibition of Cav2.2-37a currents, indicating a lack of involvement of Gi/o signaling. However, when a Src tyrosine kinase inhibitor was applied, the effect of mMOR1C was lost. Moreover, when we recorded currents using a Cav2.2-37a mutant in which tyrosine 1747 was replaced with phenylalanine (Y1747F), the agonist independent effects of mMOR1C were abolished. Altogether our findings show that Cav2.2-37a and Cav2.2-37b isoforms are subject to differential regulation by C-terminal splice variants of mMORs, and that constitutive mMOR1C activity and downstream tyrosine kinase activity exert a selective inhibition of the Cav2.2-37a splice variant, an N-type channel isoform that is highly enriched in nociceptors. Our study provides new insights into the roles of the MOR full-length C-terminal variants in modulating Cav2.2 channel isoform activities.

Dataset Information

Improved Cav2.2 Channel Inhibitors through a gem-Dimethylsulfone Bioisostere Replacement of a Labile Sulfonamide.

Publications

Improved Cav2.2 Channel Inhibitors through a gem-Dimethylsulfone Bioisostere Replacement of a Labile Sulfonamide.

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