Inhibition of human N‐ and T‐type calcium channels by an ortho‐phenoxyanilide derivative, MONIRO‐1

Abstract

This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.

Analgesic transient receptor potential vanilloid‐1‐active compounds inhibit native and recombinant T‐type calcium channels

“…Other TRPV1‐active compounds including N‐arachidonoyl dopamine, N‐arachidonoyl 5‐HT, and AM404 have also been shown to inhibit Ca v 3 channels directly (Gilmore, Heblinski, Reynolds, Kassiou, & Connor, ; Kerckhove et al, ; Ross, Gilmore, & Connor, ). The novel ortho‐phenoxylanilide derivative, MONIRO‐1, also slows recovery from inactivation kinetics of Ca v 3 channels (McArthur et al, ) suggesting a common mechanism of action between structurally related small molecules on Ca v 3 channels.…”

Closed-state inactivation and pore-blocker modulation mechanisms of human CaV2.2

“…The cells were grown in the culture dishes (d = 3.5 cm) (Thermo Fisher Scientific, USA) for 24 h and then transiently transfected with 2 mg control or mutant plasmids containing human N-type calcium channel isoform a1B, b1, a2d1 and GFP using 1.5 mg Lipofectamine 2000 Reagent (Thermo Fisher Scientific, USA). Experiments were performed 12 to 24 hours post transfection at room temperature (21 $25 C) as described previously (McArthur et al, 2018). In brief, cells were placed on a glass chamber containing 105 mM NaCl, 10 mM BaCl 2 , 10 mM HEPES, 10 mM D-Glucose, 30 mM TEA-Cl, 1 mM MgCl 2 , 5 mM CsCl, (pH = 7.3 with NaOH and osmolarity of $310 mosmol À1 ).…”

Recent advances in targeting ion channels to treat chronic pain

“…An area of optimism is the pipeline of alternative small molecules that target Ca V 3 which are showing clear preclinical promise. Expression system work has also identified the ortho‐phenoxyanilide derivative, MONIRO‐1, which showed preferential activation state‐dependent and use‐dependent block of Ca V 2.2 and Ca V 3.2 channels when tested amongst different Ca V family subunits (McArthur et al ., ).…”

“…However, there has been recent progress in MEA recordings from DRGs, including from those derived from human embryonic stem cells (Alshawaf et al ., ), which could provide important phenotypic screening platforms as a basis for identifying novel analgesics. It is often useful to support native neuronal studies with work in expression systems such as transiently transfected or stably expressed mammalian cells (Loucif et al ., ; McArthur et al ., ) or oocyte expression (Lee et al ., ; Mourot et al ., ). Such model systems, theoretically, allow ion channel pharmacology and/or biophysics to be examined in isolation.…”