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The muscarinic antagonists scopolamine and atropine are competitive antagonists at 5-HT 3 receptors

View Article: PubMed Central - PubMed

ABSTRACT

Scopolamine is a high affinity muscarinic antagonist that is used for the prevention of post-operative nausea and vomiting. 5-HT3 receptor antagonists are used for the same purpose and are structurally related to scopolamine. To examine whether 5-HT3 receptors are affected by scopolamine we examined the effects of this drug on the electrophysiological and ligand binding properties of 5-HT3A receptors expressed in Xenopus oocytes and HEK293 cells, respectively. 5-HT3 receptor-responses were reversibly inhibited by scopolamine with an IC50 of 2.09 μM. Competitive antagonism was shown by Schild plot (pA2 = 5.02) and by competition with the 5-HT3 receptor antagonists [3H]granisetron (Ki = 6.76 μM) and G-FL (Ki = 4.90 μM). The related molecule, atropine, similarly inhibited 5-HT evoked responses in oocytes with an IC50 of 1.74 μM, and competed with G-FL with a Ki of 7.94 μM. The reverse experiment revealed that granisetron also competitively bound to muscarinic receptors (Ki = 6.5 μM). In behavioural studies scopolamine is used to block muscarinic receptors and induce a cognitive deficit, and centrally administered concentrations can exceed the IC50 values found here. It is therefore possible that 5-HT3 receptors are also inhibited. Studies that utilise higher concentrations of scopolamine should be mindful of these potential off-target effects.

No MeSH data available.


Related in: MedlinePlus

The mechanism of 5-HT3 receptor inhibition by scopolamine. (A) Concentration-response curves were performed in the absence or presence of the indicated concentrations of scopolamine. The curves showed parallel dextral shifts with maximal currents restored by increasing concentrations of 5-HT. Parameters derived from these curves can be seen in Table 1. (B) A Schild plot was created from the dose ratios of the curves shown in 3A and fitted with Eq. (3) to yield a slope of 1.06 ± 0.10 (R2 = 0.97) and a pA2 of 5.03 ± 0.43 (Kb, 9.33 μM).
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fig3: The mechanism of 5-HT3 receptor inhibition by scopolamine. (A) Concentration-response curves were performed in the absence or presence of the indicated concentrations of scopolamine. The curves showed parallel dextral shifts with maximal currents restored by increasing concentrations of 5-HT. Parameters derived from these curves can be seen in Table 1. (B) A Schild plot was created from the dose ratios of the curves shown in 3A and fitted with Eq. (3) to yield a slope of 1.06 ± 0.10 (R2 = 0.97) and a pA2 of 5.03 ± 0.43 (Kb, 9.33 μM).

Mentions: Increasing concentrations of scopolamine (10 μM, 30 μM, 60 μM, 100 μM, 300 μM) caused a parallel rightward shift in the 5-HT concentration-response curve, with no change in the maximal response (Fig. 3A, Table 1). A Schild plot of these results (Fig. 3B), yielded a gradient close to 1 (1.06 ± 0.10, R2 = 0.97) and a pA2 value of 5.03 ± 0.43 (Kb = 9.33 μM). The Kb estimate was similar (2.88 μM) if the data were fitted using a nonlinear regression method (Eq. (4)) as recommended by Neubig et al. (2003) and Lew and Angus (1995). These data support a competitive mechanism of action, indicating that scopolamine binds to the orthosteric binding site.


The muscarinic antagonists scopolamine and atropine are competitive antagonists at 5-HT 3 receptors
The mechanism of 5-HT3 receptor inhibition by scopolamine. (A) Concentration-response curves were performed in the absence or presence of the indicated concentrations of scopolamine. The curves showed parallel dextral shifts with maximal currents restored by increasing concentrations of 5-HT. Parameters derived from these curves can be seen in Table 1. (B) A Schild plot was created from the dose ratios of the curves shown in 3A and fitted with Eq. (3) to yield a slope of 1.06 ± 0.10 (R2 = 0.97) and a pA2 of 5.03 ± 0.43 (Kb, 9.33 μM).
© Copyright Policy - CC BY
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4920643&req=5

fig3: The mechanism of 5-HT3 receptor inhibition by scopolamine. (A) Concentration-response curves were performed in the absence or presence of the indicated concentrations of scopolamine. The curves showed parallel dextral shifts with maximal currents restored by increasing concentrations of 5-HT. Parameters derived from these curves can be seen in Table 1. (B) A Schild plot was created from the dose ratios of the curves shown in 3A and fitted with Eq. (3) to yield a slope of 1.06 ± 0.10 (R2 = 0.97) and a pA2 of 5.03 ± 0.43 (Kb, 9.33 μM).
Mentions: Increasing concentrations of scopolamine (10 μM, 30 μM, 60 μM, 100 μM, 300 μM) caused a parallel rightward shift in the 5-HT concentration-response curve, with no change in the maximal response (Fig. 3A, Table 1). A Schild plot of these results (Fig. 3B), yielded a gradient close to 1 (1.06 ± 0.10, R2 = 0.97) and a pA2 value of 5.03 ± 0.43 (Kb = 9.33 μM). The Kb estimate was similar (2.88 μM) if the data were fitted using a nonlinear regression method (Eq. (4)) as recommended by Neubig et al. (2003) and Lew and Angus (1995). These data support a competitive mechanism of action, indicating that scopolamine binds to the orthosteric binding site.

View Article: PubMed Central - PubMed

ABSTRACT

Scopolamine is a high affinity muscarinic antagonist that is used for the prevention of post-operative nausea and vomiting. 5-HT3 receptor antagonists are used for the same purpose and are structurally related to scopolamine. To examine whether 5-HT3 receptors are affected by scopolamine we examined the effects of this drug on the electrophysiological and ligand binding properties of 5-HT3A receptors expressed in Xenopus oocytes and HEK293 cells, respectively. 5-HT3 receptor-responses were reversibly inhibited by scopolamine with an IC50 of 2.09 μM. Competitive antagonism was shown by Schild plot (pA2 = 5.02) and by competition with the 5-HT3 receptor antagonists [3H]granisetron (Ki = 6.76 μM) and G-FL (Ki = 4.90 μM). The related molecule, atropine, similarly inhibited 5-HT evoked responses in oocytes with an IC50 of 1.74 μM, and competed with G-FL with a Ki of 7.94 μM. The reverse experiment revealed that granisetron also competitively bound to muscarinic receptors (Ki = 6.5 μM). In behavioural studies scopolamine is used to block muscarinic receptors and induce a cognitive deficit, and centrally administered concentrations can exceed the IC50 values found here. It is therefore possible that 5-HT3 receptors are also inhibited. Studies that utilise higher concentrations of scopolamine should be mindful of these potential off-target effects.

No MeSH data available.


Related in: MedlinePlus