5-HT2 receptor

Effectively inhibiting the 5-HT2 coupler's coupling, volinanserin (MDL 100907) has a 300-fold coupling to the 5-HT2 coupler at a Ki of 0.36 nM. More than 300 times as much coupling is made to the 5-HT2 coupler as there is to the 5-HT1c coupler, α-1, and DA D2. The antipsychotic effect of warinserin is known [1].

Volinanserin (MDL 100907; 0.008-2.0 mg/kg, ip), at an ED50 of 0.3 mg/kg, it dramatically decreased the locomotor activity of mice stimulated by d-amphetamine without significantly affecting the mice's baseline locomotor activity. The ED50 is 10–50 mg/kg; fainting may happen during buildup. Volinanserin does not create stock market stagnation or lessen preconceptions that are induced by apomodine [1]. When used in conjunction with MK-801 (1 μg/kg), volinanserin (M100907) considerably decreased reinforcing. Additionally, when administered intraperitoneally at doses of 10, 100 μg/kg, it similarly dose-dependently countered the disruptive effects of MK-801. In the DRL 72-s regimen, volinanserin (6.25 μg/kg) compounds both the antidepressant-like effects of desipramine and the antidepressant-like effects of tranylcypromine [2].

Mice: Mice are given the test compounds intraperitoneally (i.p. ), placed individually in clear Plexiglas test cages (16 × 16 × 8 inches), and given 30 mm of acclimatization time before the test compounds' effects on spontaneous locomotor activity are measured. Haloperidol, amperozide, and volinanserin (0.008-2.0 mg/kg) are tested in six mice per dose for each of the six doses. Clozapine is tested in twelve mice per dose for six doses. In these experiments, sixty animals are provided with vehicles. After that, the boxes are put inside the activity monitors, and measurements every 30 mm are made. In order to assess how different pretreatments affect amphetamine-stimulated motor activity, four mice per test box are acclimated for 90 mm, which lowers the controls' level of spontaneous activity. The mice are then put back into the activity boxes, given an injection of amphetamine (2 mg/kg i.p.) along with the test compounds, and tested for 90 mm. In these experiments, each of the nine doses of volinanserin is tested in groups of sixteen mice, and each of the six doses of amperozide, clozapine, and haloperidol is tested in groups of sixteen mice. In these experiments, a vehicle was given to 104 mice[1]. Rats: Amperozide (1, 10 and 50 mg/kg), haloperidol (0.1, 0.3 and 1.0 mg/kg), and clozapine (1, 10 and 50 mg/kg) or Volinanserin (1, 10 and 50 mg/kg) are the medications and dosages used. These experiments are conducted with five rats per dose, five of which receive a vehicle. After administering an intraperitoneal injection, rats are given a 30 mm dose. Subsequently, they are gently placed into a transparent Plexiglas enclosure measuring 30 × 30 × 15 cm, with both front limbs resting on top of a horizontal aluminum rod with a diameter of 1.2 cm. Across the plastic enclosure, the rod is centered seven centimeters above the ground. Recorded to the closest second is the amount of time each rat spent with its hind legs on the ground and its front limbs raised on the rod. The appropriate post-hoc tests are conducted after the data are analyzed using analysis of variance[1].

[1]. Sorensen SM, et al. Characterization of the 5-HT2 receptor antagonist MDL 100907 as a putative atypical antipsychotic: behavioral, electrophysiological and neurochemical studies. J Pharmacol Exp Ther. 1993 Aug;266(2):684-91.
[2]. Ardayfio PA, et al. The 5-hydroxytryptamine2A receptor antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl-4-piperidinemethanol (M100907) attenuates impulsivity after both drug-induced disruption (dizocilpine) and enhancement (antidepressant drugs) of differential-reinforcement-of-low-rate 72-s behavior in the rat. J Pharmacol Exp Ther. 2008 Dec;327(3):891-7.

Progress toward understanding the role of the 5-hydroxytryptamine (5-HT)2 receptor in the therapy for schizophrenia has been hampered by the lack of highly selective antagonists. We now report on the effects of MDL 100,907 [R(+)-alpha-(2,3-dimethoxyphenyl)-1- [2-(4-fluorophenylethyl)]-4-piperidine-methanol], a highly selective and potent 5-HT2 receptor antagonist, in behavioral, electrophysiological and neurochemical models of antipsychotic activity and extrapyramidal side-effect liability. In mice, MDL 100,907 blocked amphetamine-stimulated locomotion at doses that did not significantly affect apomorphine-stimulated climbing behavior. Neither MDL 100,907 nor clozapine reduced apomorphine-induced stereotypies or produced catalepsy in rats. MDL 100,907 blocked the slowing of ventral tegmental area (A10) dopaminergic neurons by amphetamine but, like clozapine, produced only small increases in the number of active substantia nigra zona compacta (A9) and A10 dopamine neurons after acute administration. When administered chronically, MDL 100,907 and clozapine selectively reduced the number of spontaneously active A10 neurons, whereas haloperidol reduced activity in both the A9 and A10 regions. Consistent with their acute effect on A9 and A10 activity, neither MDL 100,907 nor clozapine increased dopamine metabolism in the striatum or nucleus accumbens, whereas acute haloperidol accelerated dopamine turnover in both regions. The administration of the dopamine uptake blocker amfonelic acid with haloperidol produced a massive increase in DA metabolism characteristic of typical antipsychotics. In contrast, MDL 100,907 and clozapine were without effect on dopamine turnover when given in the presence of amfonelic acid. These data indicate that MDL 100,907 has a clozapine-like profile of potential antipsychotic activity with low extrapyramidal sid-effect liability.[1]

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Previous work has suggested that N-methyl-d-aspartate (NMDA) receptor antagonism and 5-hydroxytryptamine (5-HT)(2A) receptor blockade may enhance and attenuate, respectively, certain types of impulsivity mediated by corticothalamostriatal circuits. More specifically, past demonstrations of synergistic "antidepressant-like" effects of a 5-HT(2A) receptor antagonist and fluoxetine on differential-reinforcement-of-low-rate (DRL) 72-s schedule of operant reinforcement may speak to the role of 5-HT(2A) receptor blockade with respect to response inhibition as an important prefrontal cortical executive function relating to motor impulsivity. To examine the dynamic range over which 5-HT(2A) receptor blockade may exert effects on impulsivity, [R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl-4-piperidinemethanol] (M100907) was examined both alone and in combination with the psychotomimetic NMDA receptor antagonist dizocilpine [e.g., (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate; MK-801] and two different antidepressants, the tricyclic antidepressant desmethylimipramine (DMI) and the monoamine oxidase inhibitor tranylcypromine in rats performing under a DRL 72-s schedule. MK-801 increased the response rate, decreased the number of reinforcers obtained, and exerted a leftward shift in the inter-response time (IRT) distribution as expected. A dose of M100907 that exerted minimal effect on DRL behavior by itself attenuated the psychotomimetic effects of MK-801. Extending previous M100907-fluoxetine observations, addition of a minimally active dose of M100907 to low doses of DMI and tranylcypromine enhanced the antidepressant-like effect of the antidepressants. Therefore, it may be that a tonic excitation of 5-HT(2A) receptors modulates impulsivity and function of corticothalamostriatal circuits over an extensive dynamic range.[2]

C22H28FNO3

373.461030006409

373.205

C, 70.75; H, 7.56; F, 5.09; N, 3.75; O, 12.85

175673-57-1

Volinanserin;139290-65-6

11953651

Typically exists as solid at room temperature

3.768

1

5

7

27

422

1

FC1=CC=C(CCN2CCC([C@@H](C3=CC=CC(OC)=C3OC)O)CC2)C=C1

HXTGXYRHXAGCFP-NRFANRHFSA-N

InChI=1S/C22H28FNO3/c1-26-20-5-3-4-19(22(20)27-2)21(25)17-11-14-24(15-12-17)13-10-16-6-8-18(23)9-7-16/h3-9,17,21,25H,10-15H2,1-2H3/t21-/m0/s1

(S)-(2,3-dimethoxyphenyl)-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol

(-)-MDL 100907; (S)-Volinanserin; MDL 100009; (S)-(2,3-Dimethoxyphenyl)(1-(4-fluorophenethyl)piperidin-4-yl)methanol; (alphaS)-alpha-[1-(4-Fluorophenethyl)-4-piperidinyl]-2,3-dimethoxybenzyl alcohol; (S)-(2,3-dimethoxyphenyl)-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol; SCHEMBL4227186;

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

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.

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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).

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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)

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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).

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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

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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.

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