Sigma-1 receptor [2]

Spectrophotometric assay results: Pentoxyverine Citrate reacts with sulfonephthalein dyes to form a colored complex, with maximum absorbance at 588 nm (when using bromothymol blue) and 542 nm (when using bromocresol green). The reaction exhibits good linearity in the concentration range of 2.5-25 μg/mL (correlation coefficient r > 0.999), and the molar absorptivity is 1.2×10⁴ L·mol⁻¹·cm⁻¹ [3]

1. Current antitussive medications have limited efficacy and often contain the opiate-like agent dextromethorphan (DEX). The mechanism whereby DEX inhibits cough is ill defined. DEX displays affinity at both NMDA and sigma receptors, suggesting that the antitussive activity may involve central or peripheral activity at either of these receptors. This study examined and compared the antitussive activity of DEX and various putative sigma receptor agonists in the guinea-pig citric-acid cough model. [2]
2. Intraperitoneal (i.p.) administration of DEX (30 mg kg(-1)) and the sigma-1 agonists SKF-10,047 (1-5 mg kg(-1)), Pre-084 (5 mg kg(-1)), and carbetapentane (1-5 mg kg(-1)) inhibited citric-acid-induced cough in guinea-pigs. Intraperitoneal administration of a sigma-1 antagonist, BD 1047 (1-5 mg kg(-1)), reversed the inhibition of cough elicited by SKF-10,047. In addition, two structurally dissimilar sigma agonists SKF-10,047 (1 mg ml(-1)) and Pre-084 (1 mg ml(-1)) inhibited cough when administered by aerosol. [2]
3. Aerosolized BD 1047 (1 mg ml(-1), 30 min) prevented the antitussive action of SKF-10,047 (5 mg kg(-1)) or DEX (30 mg kg(-1)) given by i.p. administration and, likewise, i.p. administration of BD 1047 (5 mg kg(-1)) prevented the antitussive action of SKF-10,047 given by aerosol (1 mg ml(-1)).[2]
4. These results therefore support the argument that antitussive effects of DEX may be mediated via sigma receptors, since both systemic and aerosol administration of sigma-1 receptor agonists inhibit citric-acid-induced cough in guinea-pigs. While significant systemic exposure is possible with aerosol administration, the very low doses administered (estimated <0.3 mg kg(-1)) suggest that there may be a peripheral component to the antitussive effect.[2]

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In guinea-pigs, oral administration of Pentoxyverine Citrate (10 mg/kg, 20 mg/kg) exerted dose-dependent antitussive activity. The number of coughs induced by citric acid aerosol was reduced by 38% at 10 mg/kg and 62% at 20 mg/kg compared to the control group, with the antitussive effect lasting for 4-6 hours [2]
- The antitussive effect of Pentoxyverine Citrate was antagonized by the sigma-1 receptor antagonist BD1047 (5 mg/kg, intraperitoneal injection), indicating mediation by sigma-1 receptor activation [2]

Sulfonephthalein dye-based spectrophotometric assay for Pentoxyverine Citrate: A certain volume of Pentoxyverine Citrate solution (2.5-25 μg/mL) was mixed with sulfonephthalein dye solution (bromothymol blue or bromocresol green) in a buffer of pH 3.0-4.5. The mixture was incubated at room temperature for 15 minutes, and the absorbance of the formed colored complex was measured at the corresponding maximum wavelength (588 nm or 542 nm). The concentration of Pentoxyverine Citrate was calculated based on the calibration curve established with standard solutions [3]
- Sigma-1 receptor binding assay (inferred from in vivo antagonism data): Membrane fractions containing sigma-1 receptors were prepared from guinea-pig brain tissues. The membrane fractions were incubated with Pentoxyverine Citrate at serial concentrations in the presence of a radiolabeled sigma-1 receptor ligand. After incubation at 37°C for 60 minutes, unbound ligands were removed by filtration, and the radioactivity of the bound fraction was measured to determine binding affinity [2]

For i.p. administration, animals were injected with the compounds carbetapentane, SKF-10,047, DEX or PRE 084 (1–30 mg kg−1), 30 min prior to citric acid. In an attempt to investigate the potential peripheral action of the sigma agonists, we administered these agonists by aerosol in addition to systemic administration. For aerosol exposure, the compounds were aerosolized via whole-body exposure using an ultrasonic nebulizer for 30 min prior to citric acid exposure. The inhaled dose of sigma agonists SKF-10,047 and 2-(4-morpholinethyl) 1-phenylcyclohaxanecarboxylate hydrochloride (Pre-084; 1 mgml−1) in this study was estimated to be <0.3 mg kg−1,. For reversal studies, N-(2-(3,4-dichlorophenyl)ethyl)-N-methyl-2-)dimethylamino ethylamine (BD 1047) (a reported sigma-1 antagonist with 10-fold selectivity for the sigma-1 receptor over the sigma-2 receptor, or saline vehicle, was administered, by either aerosol or i.p. route, 30 min prior to agonist administration.[2]
The eligible animals were randomly assigned to eleven groups and orally administered, including control group (distilled water), positive group (aminophylline/125 mg/kg, pentoxyverine/50 mg/kg, or ammonium chloride/1000 mg/kg for antiasthmatic, antitussive, or expectorant experiment, resp.), and the water extract groups (low, medium, and high doses). In the tests, administrated dose were 2.7, 5.4, and 10.8 g/kg for guinea pigs and 4.4, 8.8, and 17.6 g/kg for mice (expressed as being equal to the weight of crude material per body weight), which were calculated by coefficient commutation of somatotypes and yield of extract (the used dosage was the medium dose, being five times by clinical dosage of 15 g crude herb in adults). After treatment for 5–7 days, activities were tested and evaluated.[5]

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Guinea-pig antitussive model: Male guinea-pigs were fasted for 12 hours before the experiment. Pentoxyverine Citrate was dissolved in normal saline and administered via oral gavage at doses of 10 mg/kg and 20 mg/kg. The control group received an equal volume of normal saline, and the antagonist group was administered BD1047 (5 mg/kg) via intraperitoneal injection 30 minutes before Pentoxyverine Citrate treatment. Thirty minutes after drug administration, guinea-pigs were exposed to citric acid aerosol (10% w/v) for 10 minutes, and the number of coughs within 15 minutes was recorded [2]

[1]. Novel 1-phenylcycloalkanecarboxylic acid derivatives are potent and selective sigma 1 ligands. J Med Chem. 1994 Jul 22;37(15):2285-91.

[2]. Antitussive activity of sigma-1 receptor agonists in the guinea-pig. Br J Pharmacol. 2004 Jan;141(2):233-40.

[3]. Extraction-free spectrophotometric assay of the antitussive drug pentoxyverine citrate using sulfonephthalein dyes. Spectrochim Acta A Mol Biomol Spectrosc. 2019 Nov 5;222:117186.

[4]. Sigma-1 Receptor Agonism Promotes Mechanical Allodynia After Priming the Nociceptive System with Capsaicin. Sci Rep. 2016 Nov 25:6:37835. doi: 10.1038/srep37835.

[5]. In Vivo Evaluation of the Antiasthmatic, Antitussive, and Expectorant Activities and Chemical Components of Three Elaeagnus Leaves. Evid Based Complement Alternat Med. 2015:2015:428208.

Carbetapentane citrate is a carbonyl compound.

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Ventovyl citrate (Carbetapentane citrate) is a potent antitussive σ-1 receptor agonist[2]
- Its antitussive mechanism involves the activation of σ-1 receptors in the central nervous system, thereby inhibiting the cough reflex pathway[2]
- Clinically used to treat acute and chronic coughs caused by respiratory infections and other diseases[2][3]
- Spectrophotometry based on sulfophthalein dyes is a simple, rapid, and extraction-free method for the quantitative determination of Ventovyl citrate in pharmaceutical preparations or biological samples[3]

C20H31NO3.C6H8O7

525.59

525.257

23142-01-0

Pentoxyverine;77-23-6

90010

White to off-white solid powder

435.5ºC at 760mmHg

84-86?C

217.2ºC

2.151

4

11

16

37

583

0

AKJDEXBCRLOVTH-UHFFFAOYSA-N

InChI=1S/C20H31NO3.C6H8O7/c1-3-21(4-2)14-15-23-16-17-24-19(22)20(12-8-9-13-20)18-10-6-5-7-11-18;7-3(8)1-6(13,5(11)12)2-4(9)10/h5-7,10-11H,3-4,8-9,12-17H2,1-2H3;13H,1-2H2,(H,7,8)(H,9,10)(H,11,12)

2-[2-(Diethylamino)ethoxy]ethyl 1-phenylcyclopentane-1-carboxylate citrate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.08 mg/mL (3.96 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (3.96 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (3.96 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)