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 being investigated in the clinical trial NCT00464243 (Efficacy and safety of Volinanserin for sleep maintenance insomnia – Polysomnography study).

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Due to the lack of highly selective antagonists, progress in understanding the role of serotonin (5-HT)2 receptors in the treatment of schizophrenia has been slow. We now report the effects of the highly selective and potent 5-HT2 receptor antagonist MDL 100,907 [R(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol] in behavioral, electrophysiological, and neurochemical models of antipsychotic activity and susceptibility to extrapyramidal side effects. In mice, MDL 100,907 blocked amphetamine-stimulated motor activity at doses that did not significantly affect climbing behavior stimulated by apomorphine. MDL 100,907 and clozapine, on average, did not alleviate apomorphine-induced stereotyped behavior or induce rigidity in rats. MDL 100,907 blocks the inhibitory effect of amphetamine on dopaminergic neurons in the ventral tegmental area (A10), but similar to clozapine, acute administration only slightly increases the activity of dopaminergic neurons in the substantia nigra pars compacta (A9) and A10. With long-term administration, MDL 100,907 and clozapine selectively reduce the number of spontaneously active A10 neurons, while haloperidol simultaneously reduces neuronal activity in both A9 and A10. Consistent with their acute effects on A9 and A10 activity, MDL 100,907 and clozapine do not increase dopamine metabolism in the striatum or nucleus accumbens, while acute haloperidol accelerates dopamine turnover in these two regions. The combined use of the dopamine uptake blocker aminophenol with haloperidol results in a significant increase in dopamine metabolism, a characteristic feature of typical antipsychotic drugs. Conversely, MDL 100,907 and clozapine had no effect on dopamine turnover in the presence of aminophenol. These data suggest that MDL 100,907 has potential antipsychotic activity similar to clozapine with a lower risk of extrapyramidal side effects. [1]

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Previous studies have shown that N-methyl-D-aspartate (NMDA) receptor antagonists and serotonin (5-HT) 2A receptor blockers may enhance and attenuate certain types of impulsivity mediated by the corticothalamic-striatal circuit, respectively. More specifically, 5-HT2A receptor antagonists and fluoxetine have previously been shown to have a synergistic “antidepressant-like” effect in a 72-second operant reinforcement procedure of low-frequency differential reinforcement (DRL), which may suggest that 5-HT2A receptor blockers play an important role in response inhibition, an important prefrontal cortical executive function associated with motor impulsivity. To examine the dynamic range of the effects of 5-HT(2A) receptor blockade on impulsivity, we tested it alone and in combination with the psychoactive NMDA receptor antagonist dezoczepine [e.g., (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine maleate; MK-801] and two different antidepressants, namely the tricyclic antidepressant desipramine (DMI) and the monoamine oxidase inhibitor transphenylcyclopropamine, in rats under a 72-second DRL reinforcement program. As expected, MK-801 increased response rate, reduced the number of reinforcers, and shifted the inter-response time (IRT) distribution to the left. The psychopathic effects of MK-801 were attenuated by a dose of M100907 alone, which had minimal effect on DRL behavior. Based on previous observations of M100907-fluoxetine combination therapy, adding the lowest effective dose of M100907 to low doses of DMI and tranylcypromine enhanced the antidepressant-like effects of the antidepressants. Therefore, sustained excitation of 5-HT(2A) receptors may modulate impulsivity and the function of the corticothalamic-striatal circuit over a wide dynamic range. [2]

C22H28FNO3

373.46

373.205

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

1

5

7

27

422

1

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

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; 139290-65-6; Volinanserin [INN]; MDL100.907; MDL-100,907; 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.)