5-HT2C Receptor Dopamine Receptor

Mesulergine is a potent 5-HT receptor antagonist mainly at the 5-HTlC postsynaptic receptor site (currently known as 5HT2C because of its structural similarity to the 5-HT2 family (Hoyer et.a1.,1994, Peroutka.1995) which leads to significant increase of food consumption at 4hn basis (Dourish et.al. 1989a). This compound was synthesized as an antiparkinson agent as it exerts dopamine agonistic properties. [1]

---

Mesulergine was found to antagonise D1-receptor responses at micromolar, and D2-receptor responses at nanomolar concentrations. In contrast, the bidemethylated metabolite of mesulergine stimulated both D1- and D2-receptors at micromolar and nanomolar concentrations, respectively. These in vitro results suggest that at dopamine receptors, mesulergine has antagonistic effects and that the late agonistic effects seen in vivo are mostly due to metabolic conversion into a potent dopaminomimetic drug.[3]

1.The effects of mesulergine, a 5-hydroxytryptamine (5-HT) receptor antagonist with dopamine (DA) agonistic properties, on rats diet selection over a seven day period and on 5-HT and DA turnover was studied.
2.Three groups of male Wistar rats were individually caged and ad libitum fed with a standard (SD) and 50% sweet carbohydrate enriched diet (CED). Food intake was measured daily 4hrs and 24hrs after ip injections of mesulergine (1 and 3mg/kg) or vehicle. 5-HT and 5-HIAA in hypothalamus (Hy), Striatum (St) and hippocampus (Hi) as well as DA and DOPAC in (Hy) and (St) were assayed at the 8th day of the experiment.
3.There was a dose dependent increase of SD consumption 4hrs after mesulergine treatment while the CED remained unchanged with total food intake dose dependently increased as a consequence. At 24hrs measurements SD consumption was increased only for the dose of 1mg/kg of mesulergine, while a dose dependent decrease of CED intake was observed. Total food intake was unchanged for the dose of 1mg/kg and decreased with the dose of 3mg/kg consequently. A dose dependent decrease of rats body weight was observed too.
4.A significant increase of 5-HIAA5-HTratio in (Hy) and (St) for the dose of 1 mg/kg and in (Hi) for the dose of 3mg/kg with no changes of DA turnover were found.
5.The above data suggest a dual mode of action of mesulergine presented as a short term hyperphagia due to simultaneous antiserotonergic and dopaminergic activity and long-term hypophagia due to long-term agonistic effects of dopaminergic neurons. [1]

---

Administration of mCPP impaired STM, LTM and LA of rats. Mesulergine injected rats exhibited no alteration in memory functions. However, when it was injected with mCPP then there were no memory deficits induced by mCPP. Conclusion: Ability of 5-HT2C receptor antagonist mesulergine to block the memory impairment effect of mCPP indicated an important regulatory role of 5-HT2C receptors in cognitive processes. [2]

Procedure [1]
Three days prior to the start of the experimental treatment the rats were acclimatized and were trained to consume their food ad libidum from two different diet groups for 24hrs after treatment of sham ip injections at times corresponding to subsequent drug administration (9 a.m.). At the start of the experiment the animals were randomly sorted into 3 groups that received the vehicle, mesulergine 1 mg/kg and 3mg/kg. Each group was supplied with the following pair of pulverized and well mixed food compositions. Feeder I: Standard rat diet (SD), Fedder II: Carbohydrate enriched diet (CED) (50% SD+50% Glucose). The standard laboratory rat diet had the following composition: proteins 20%, fat 2-5%, cellulose 6%, ash 18%, calcium l-l .8%, phosphorus 0,8-l% and minerals, while humidity was 18%. Animals were given simultaneous access to each pair of diets 30min after ip injections of the vehicle or mesulergine (lmgkg and 3mgIkg). Feeders with preweighed food were weighed at 4hrs and 24hrs basis. The position of the feeders was alternated daily. Body weight was measured daily. Animals were decapitated on the eighth day of the experiment between l-2p.m., 2hrs after the last dose of the vehicle or the drug. The brains were rapidly removed and hypothalamic, hippocampal and striatal regions were rapidly isolated according to Glowinski and lversen (1966) method. 5-HT, DA and their metabolttes were assayed using High Liquid Pressure Chromatography (Adams and Marden 1982). 5-HIAAfS-HT and DOPAC/DA ratios (as indirect indices of S-HT and DA turnover) were calculated.

Drua Administration [1]
The experimental animals were injected ip with mesulergine at doses 1 and 3mg/kg. Mesulergine was dispersed in normal saline and the control group was treated with normal saline. Solutions were freshly prepared before use. The injected volume was 0.1 ml/l OOg rat body weight.

---

Twenty-four male albino Wistar rats were used in this study. The agonist and antagonist (mCPP and mesulergine) were injected intraperitoneally at a dose 3.0 mg/kg in volumes of 1 ml/kg. Control animals were injected with saline (1 ml/kg). Animals were randomly divided into four groups (n=6). 1st being control group, 2nd being mCPP injected group, 3rd being mesulergine injected group and 4th group being injected with both mesulergine and mCPP. Behavioural activities of rats were monitored after 30 minutes of injection. For assessment of memory functions, water maze apparatus was used. [2]

[1].Effects of mesulergine treatment on diet selection, brain serotonin (5-HT) and dopamine (DA) turnover in free feeding rats. Prog Neuropsychopharmacol Biol Psychiatry. 1998 Jul;22(5):803-13.

[2].Influence of serotonergic 5-HT2C receptor antagonist mesulergine in the reversal of memory deficits induced by mCPP. J Coll Physicians Surg Pak. 2012 Feb;22(2):75-9.

[3]. Mesulergine and its 1,20-N,N-bidemethylated metabolite interact directly with D1- and D2-receptors. Eur J Pharmacol . 1983 Nov 11;95(1-2):101-7. d

Objective: To determine the effect of non-selective 5-HT2C antagonist mesulergine and 5-HT2C agonist mCPP (metachlorophenylpiperazine) on learning acquisition (LA), short-term memory (STM) and long-term memory (LTM). Study design: Experimental study. Place and duration of study: Department of Biochemistry, University of Karachi, from December 2009 to June 2010. Methodology: Twenty-four male albino Wistar rats were used in this study. The agonist and antagonist (mCPP and mesulergine) were injected intraperitoneally at a dose 3.0 mg/kg in volumes of 1 ml/kg. Control animals were injected with saline (1 ml/kg). Animals were randomly divided into four groups (n=6). 1st being control group, 2nd being mCPP injected group, 3rd being mesulergine injected group and 4th group being injected with both mesulergine and mCPP. Behavioural activities of rats were monitored after 30 minutes of injection. For assessment of memory functions, water maze apparatus was used. Results: Administration of mCPP impaired STM, LTM and LA of rats. Mesulergine injected rats exhibited no alteration in memory functions. However, when it was injected with mCPP then there were no memory deficits induced by mCPP. Conclusion: Ability of 5-HT2C receptor antagonist mesulergine to block the memory impairment effect of mCPP indicated an important regulatory role of 5-HT2C receptors in cognitive processes. [2]

---

Mesulergine (CU 32-085), an 8 alpha-aminoergoline, has been reported to influence striatal dopamine turnover in a time-dependent biphasic manner, suggesting initial dopamine antagonistic and late dopamine agonistic effects. To clarify whether these opposing in vivo effects are due to a metabolic conversion in vivo or reflect mixed antagonist/agonist effects expressed at different dose levels, mesulergine and a 1,20-N,N-bidemethylated metabolite, identified in rat urine, were investigated in functional dopamine receptor models. Dopamine-sensitive adenylate cyclase in homogenates of rat striatum and modulation of electrically evoked tritium overflow from rat striatal slices previously labelled with [3H]choline were used as tests for D1- and D2-receptors, respectively. Mesulergine was found to antagonise D1-receptor responses at micromolar, and D2-receptor responses at nanomolar concentrations. In contrast, the bidemethylated metabolite of mesulergine stimulated both D1- and D2-receptors at micromolar and nanomolar concentrations, respectively. These in vitro results suggest that at dopamine receptors, mesulergine has antagonistic effects and that the late agonistic effects seen in vivo are mostly due to metabolic conversion into a potent dopaminomimetic drug. [3]

C18H27CLN4O2S

398.95

362.178

C, 54.19; H, 6.82; Cl, 8.89; N, 14.04; O, 8.02; S, 8.04

72786-12-0

64795-35-3 (Parent/free base)

155746

Typically exists as solid at room temperature

1.38g/cm3

545.7ºC at 760mmHg

283.8ºC

2.696

2

5

3

26

605

3

CN1C[C@H](C[C@H]2[C@H]1CC3=CN(C4=CC=CC2=C34)C)NS(=O)(=O)N(C)C.Cl

HANSYUJEPWNHIM-IVMONYBCSA-N

InChI=1S/C18H26N4O2S.ClH/c1-20(2)25(23,24)19-13-9-15-14-6-5-7-16-18(14)12(10-21(16)3)8-17(15)22(4)11-13;/h5-7,10,13,15,17,19H,8-9,11H2,1-4H3;1H/t13-,15+,17+;/m0./s1

(6aR,9S,10aR)-9-(dimethylsulfamoylamino)-4,7-dimethyl-6,6a,8,9,10,10a-hexahydroindolo[4,3-fg]quinoline;hydrochloride

Mesulergine hydrochloride; 72786-12-0; Mesulergine HCl; CU-32-085; Mesulergine (hydrochloride); CU 32-085; (6aR,9S,10aR)-9-(dimethylsulfamoylamino)-4,7-dimethyl-6,6a,8,9,10,10a-hexahydroindolo[4,3-fg]quinoline;hydrochloride; CU32-085;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

Typically soluble in DMSO (e.g. 10 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

---

Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

View More

Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

---

Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

View More

Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

---

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

---

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