Abongwa M et al. (2018), Monepantel is a non-competitive antagonist of n...

XB-ART-54580

Int J Parasitol Drugs Drug Resist 2018 Apr 01;81:36-42. doi: 10.1016/j.ijpddr.2017.12.001.

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Monepantel is a non-competitive antagonist of nicotinic acetylcholine receptors from Ascaris suum and Oesophagostomum dentatum.

Abongwa M , Marjanovic DS , Tipton JG , Zheng F , Martin RJ , Trailovic SM , Robertson AP .

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Zolvix® is a recently introduced anthelmintic drench containing monepantel as the active ingredient. Monepantel is a positive allosteric modulator of DEG-3/DES-2 type nicotinic acetylcholine receptors (nAChRs) in several nematode species. The drug has been reported to produce hypercontraction of Caenorhabditis elegans and Haemonchus contortus somatic muscle. We investigated the effects of monepantel on nAChRs from Ascaris suum and Oesophagostomum dentatum heterologously expressed in Xenopus laevis oocytes. Using two-electrode voltage-clamp electrophysiology, we studied the effects of monepantel on a nicotine preferring homomeric nAChR subtype from A. suum comprising of ACR-16; a pyrantel/tribendimidine preferring heteromeric subtype from O. dentatum comprising UNC-29, UNC-38 and UNC-63 subunits; and a levamisole preferring subtype (O. dentatum) comprising UNC-29, UNC-38, UNC-63 and ACR-8 subunits. For each subtype tested, monepantel applied in isolation produced no measurable currents thereby ruling out an agonist action. When monepantel was continuously applied, it reduced the amplitude of acetylcholine induced currents in a concentration-dependent manner. In all three subtypes, monepantel acted as a non-competitive antagonist on the expressed receptors. ACR-16 from A. suum was particularly sensitive to monepantel inhibition (IC50 values: 1.6 ± 3.1 nM and 0.2 ± 2.3 μM). We also investigated the effects of monepantel on muscle flaps isolated from adult A. suum. The drug did not significantly increase baseline tension when applied on its own. As with acetylcholine induced currents in the heterologously expressed receptors, contractions induced by acetylcholine were antagonized by monepantel. Further investigation revealed that the inhibition was a mixture of competitive and non-competitive antagonism. Our findings suggest that monepantel is active on multiple nAChR subtypes.

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	Fig. 1. Chemical structure of monepantel [N-[(2S)-2-cyano-1-[5-cyano-2-(trifluoromethyl)phenoxy]propan-2-yl]-4-(trifluoromethylsulfanyl)benzamide].
	Fig. 2. Inhibitory effects of monepantel on Asu-ACR-16 (nicotine sensitive receptors). (A) Sample traces for two-electrode voltage-clamp recording for oocyte responses to acetylcholine for oocytes expressing Asu-ACR-16 subtype nAChR. (B) Sample traces for two-electrode voltage-clamp recording for oocyte responses to acetylcholine in the presence of 1 μM monepantel. (C) Concentration-response plots for acetylcholine in the absence and presence of monepantel. Control acetylcholine (n = 4, black); in the presence of 0.3 nM monepantel (n = 4, light blue); 3 nM monepantel (n = 4, light purple); 30 nM monepantel (n = 4, orange), 0.1 μM monepantel (n = 5, olive green), 0.3 μM monepantel (n = 4, purple), 0.5 μM monepantel (n = 4, pink) and 1 μM monepantel (n = 4, green). (D) Bar chart showing mean ± s.e.m. (n = 4–5) for Rmax for acetylcholine and monepantel. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
	Fig. 3. Inhibitory effects of monepantel on Ode pyrantel/tribendimidine preferring nAChRs. (A) Sample traces for two-electrode voltage-clamp recording for oocyte responses to acetylcholine for oocytes expressing Ode pyrantel/tribendimidine subtype nAChR. (B) Sample traces for two-electrode voltage-clamp recording for oocyte responses to acetylcholine in the presence of 0.3 μM monepantel. (C) Concentration-response plots for acetylcholine in the absence and presence of monepantel. Control acetylcholine (n = 4, black); in the presence of 0.3 μM monepantel (n = 5, purple); 1 μM monepantel (n = 4, green); 3 μM monepantel (n = 4, red) and 10 μM monepantel (n = 4, blue). (D) Bar chart showing mean ± s.e.m. (n = 4–5) for Rmax for acetylcholine and monepantel. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
	Fig. 4. Monepantel inhibits Ode levamisole preferring receptors. (A) Sample traces for two-electrode voltage-clamp recording for oocyte responses to acetylcholine for oocytes expressing Ode levamisole subtype nAChR. (B) Sample traces for two-electrode voltage-clamp recording for oocyte responses to acetylcholine in the presence of 3 μM monepantel. (C) Concentration-response plots for acetylcholine in the absence and presence of monepantel. Control acetylcholine (n = 4, black); in the presence of 1 μM monepantel (n = 4, green); 3 μM monepantel (n = 4, red); 10 μM monepantel (n = 4, blue) and 30 μM monepantel (n = 5, grey). (D) Bar chart showing mean ± s.e.m. (n = 4–5) for Rmax for acetylcholine and monepantel. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
	Fig. 5. Inhibition of Ascaris suum muscle flap contractions by monepantel. (A) Isometric contractions of A. suum muscle flap following application of increasing acetylcholine concentrations and antagonism by 10 μM (blue bar) and 30 μM (grey bar) monepantel. (B) Concentration-contraction response plots for acetylcholine showing mean ± s.e.m. bars. Control acetylcholine (n = 11, black); in the presence of 1 μM monepantel (n = 6, green), 3 μM monepantel (n = 6, red), 10 μM monepantel (n = 5, blue) and 30 μM monepantel (n = 5, grey). (C) Inhibition curve plotted as mean ± s.e.m. (n = 4–5) maximum response versus concentration of monepantel and Hill equation fit with an IC50 of 1.6 ± 3.1 nM and 0.2 ± 2.3 μM for Asu-ACR-16, 1.7 ± 0.7 μM for Ode pyrantel/tribendimidine, and 5.0 ± 0.5 μM for Ode levamisole receptors. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

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