5-HT2 receptor ( Ki = 0.36 nM )

Volinanserin (MDL 100907) is an effective coupling inhibitor for the 5-HT2 coupler with a Ki of 0.36 nM and a 300-fold coupling to the 5-HT2 coupler. The coupling to the 5-HT2 coupler is 300 times greater than the absorption to the 5-HT1c coupler, α-1 and DA D2. Warinserin has antipsychotic activity [1].

Volinanserin (MDL 100907; 0.008-2.0 mg/kg, ip) significantly reduced the locomotor activity of mice stimulated by d-amphetamine, with an ED50 of 0.3 mg/kg, without showing a significant reduction in the baseline locomotor activity of mice. Fainting may occur during accumulation, ED50 is 10-50 mg/kg. Volinanserin does not reduce apomodine-induced stereotypes or cause stock market stagnation [1]. Volinanserin (M100907), in combination with MK-801 (1 μg/kg), significantly reduced reinforcement and (10, 100 μg/kg) also dose-dependently antagonized the disruptive effects of MK-801 in dependence via intraperitoneal injection . Volinanserin (6.25 μg/kg) potentiates the antidepressant-like effects of tranylcypromine in the DRL 72-s regimen and also potentiates the antidepressant-like effects of desipramine [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]. 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]. 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.

Volinanserin is under investigation in clinical trial NCT00464243 (Efficacy and Safety of Volinanserin on Sleep Maintenance Insomnia - Polysomnographic Study).

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Serotonin Antagonists: Drugs that bind to but do not activate serotonin receptors, thereby blocking the actions of serotonin or SEROTONIN RECEPTOR AGONISTS.

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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

373.46

373.21

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

139290-65-6

Volinanserin-d4 hydrochloride; 1217617-73-6; (S)-Volinanserin; 175673-57-1

5311271

White to yellow solid powder

1.2±0.1 g/cm3

499.4±45.0 °C at 760 mmHg

89-91ºC

255.8±28.7 °C

0.0±1.3 mmHg at 25°C

1.557

3.56

41.93

COC1=CC=CC(=C1OC)[C@@H](C2CCN(CC2)CCC3=CC=C(C=C3)F)O

HXTGXYRHXAGCFP-OAQYLSRUSA-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-/m1/s1

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

M-100907; M-100907; Volinanserin; MDL-100907; MDL 100907; Mdl 100907; M100907; MDL-100907; Volinanserin [INN]; (R)-(2,3-Dimethoxyphenyl)(1-(4-fluorophenethyl)piperidin-4-yl)methanol; MDL100.907;MDL100907

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)

DMSO: 50~75 mg/mL (133.9~200.8 mM)
Ethanol: ~75 mg/mL

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.69 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 25.0 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: ≥ 2.5 mg/mL (6.69 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 25.0 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: ≥ 2.5 mg/mL (6.69 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 25.0 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.)