BMY-14802 primarily targets sigma receptors, functioning as a sigma ligand. Additionally, this compound binds to 5-HT1A receptors and exhibits 5-HT1A receptor agonist activity, inhibiting the firing of dorsal raphe serotonergic neurons. BMY-14802 also functionally modulates responses mediated by the NMDA receptor complex but shows very low affinity for dopamine D₂ receptors and phencyclidine receptors.
Serotonin 5-HT1A receptor (agonist, IC50 = 320 nM); Sigma-1 receptor (antagonist, IC50 = 112 nM); Adrenergic α-1 receptor (agonist, IC50 = 460 nM). [1]

Like other 5-HT1A agonists, BMY-14802 hydrochloride modifies 5-HT-mediated behavior in a 5-HT1A-sensitive way by influencing the firing of serotonergic and catecholaminergic neurons. D2 receptors are not significantly favored by BMY-14802 hydrochloride [3].

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BMY-14802 demonstrates moderate affinity for sigma receptors in vitro while exhibiting very low affinity for dopamine D₂ receptors, making it an attractive candidate as an atypical antipsychotic. The compound also binds to 5-HT1A receptors and acts as an agonist. In neurochemical studies, BMY-14802 (10-50 mg/kg) does not produce any stereotyped behavior, ataxia, or seizures, suggesting a favorable in vitro safety profile.

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BMY-14802 (5 mg/kg, 10 mg/kg, or 20 mg/kg intraperitoneally; once) hydrochloride is effective in decreasing D1 and D2 receptor-induced dyskinesias and demonstrates antidyskinetic activity over a 4-fold dose range in L-DOPA-induced dyskinesia (LID). Crucially, BMY-14802 hydrochloride did not diminish L-DOPA's ability to prevent lesion-induced akinesia when administered at anti-LID dosages [2].

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BMY-14802 exhibits multiple in vivo activities in animal models. Regarding antipsychotic effects, BMY-14802 (5-30 mg/kg) antagonizes amphetamine-induced disruption of latent inhibition in rats and enhances latent inhibition under low preexposure conditions, suggesting potential antipsychotic properties. For neuroprotection, pretreatment with BMY-14802 (10-50 mg/kg) 30 minutes prior to bilateral carotid artery occlusion significantly protects against ischemia-induced hippocampal neuronal loss in gerbils. In the serotonergic system, BMY-14802 (5-20 mg/kg) induces dose-dependent decreases in extracellular 5-HT concentrations in the dorsal raphe and hippocampus, an effect completely antagonized by the specific 5-HT1A antagonist WAY-100635. Electrophysiological studies show that this compound inhibits serotonergic dorsal raphe neuron firing (i.v. ED₅₀ = 0.19 mg/kg) and produces mild excitation of noradrenergic locus coeruleus neurons. Furthermore, BMY-14802 (30 mg/kg) reverses the reduction of striatal dopamine release induced by the sigma receptor agonist (+)-3PPP.

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In the unilateral 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease, pre-treatment with BMY-14802 (15 mg/kg, i.p.) significantly suppressed the expression of L-DOPA-induced abnormal involuntary movements (AIMs). This effect was observed as a reduction in the summed limb, axial, and oral AIM scores over a 3-hour test session following L-DOPA administration. [1]
The AIM-suppressing effect of BMY-14802 (15 mg/kg, i.p.) was dose-dependently prevented by co-administration of the selective 5-HT1A antagonist WAY-100635 (0.5 mg/kg, i.p.), but not by the α-1 adrenergic antagonist prazosin (0.1 mg/kg, i.p.). This suggests that the effect is mediated through the 5-HT1A receptor. [1]
BMY-14802 (15 mg/kg, i.p.) also suppressed L-DOPA-induced contraversive rotational behavior in the 6-OHDA rat model. This effect on rotation was also prevented by WAY-100635 (0.5 mg/kg, i.p.), further supporting a 5-HT1A-mediated mechanism. [1]
In contrast to BMY-14802, several other compounds with activity at sigma receptors (sigma-1 antagonist BD-1047, sigma-2 antagonist SM-21, sigma-1/2 agonist DTG, sigma-1 agonists DHEA, carbetapentane, and opipramol, and the 5-α-reductase inhibitor finasteride which elevates the sigma-1 antagonist progesterone) did not suppress AIM expression in the 6-OHDA rat model. [1]

The receptor binding properties of BMY-14802 can be assessed using radioligand binding assays. Membrane homogenates from cells expressing the target receptors (e.g., sigma receptors, 5-HT1A receptors, or dopamine D₂ receptors) are incubated with radiolabeled ligands (e.g., [³H]DTG for sigma receptors, [³H]8-OH-DPAT for 5-HT1A receptors) and various concentrations of BMY-14802 in binding buffer. After incubation at room temperature for 60 minutes, the reaction is terminated by rapid vacuum filtration, and filters are washed with ice-cold buffer. After drying, retained radioactivity on filters is measured using a liquid scintillation counter to calculate specific binding percentages, and IC₅₀ and Ki values are obtained by fitting competition binding curves.

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Exponentially growing neurons or cell lines stably expressing target receptors (e.g., CHO or HEK293 cells) are seeded into 24-well or 96-well culture plates at appropriate densities (1-5×10⁴ cells/well) in medium containing 10% fetal bovine serum and cultured overnight. After serum starvation for synchronization (12 hours), various concentrations of BMY-14802 (e.g., 0.01-100 μM) are added. For 5-HT release assays, microdialysis can be used to collect extracellular fluid, and 5-HT, 5-HIAA, and HVA concentrations are determined by high-performance liquid chromatography with electrochemical detection. For cAMP detection, intracellular cAMP accumulation can be measured using ELISA or radioimmunoassay.

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6-OHDA Lesion Model:** Male Sprague-Dawley rats received unilateral infusions of 6-OHDA (22.8 μg/2μl per site) into two sites of the right medial forebrain bundle to model Parkinson's disease. Rats with significant hemi-parkinsonism, defined as an average of ≥5 turns/min over 10 minutes in response to amphetamine (5 mg/kg, i.p.), were selected for the study. [1]
* **L-DOPA Treatment and AIM Induction:** Selected rats were treated once daily for 21 days with L-DOPA methyl ester HCl (7.5 mg/kg, i.p.) combined with benserazide (15 mg/kg, i.p.) and ascorbic acid (2.6 mg/kg, i.p.) to induce stable AIM expression. Following this, they were maintained on a regimen of 2 L-DOPA injections per week. [1]
* **Drug Testing Protocol:** To test the efficacy of BMY-14802 and other compounds on AIM expression, test drugs were administered during the maintenance phase. BMY-14802 (15 mg/kg), buspirone (1, 4, 10 mg/kg), and other sigma agents were dissolved in either milliQ water, 0.9% saline, or β-cyclodextrin solutions. They were administered intraperitoneally (i.p.) at a volume of 1 ml/100 gm body weight, 30 minutes prior to L-DOPA injection. Finasteride was administered 22 hours prior to L-DOPA at a volume of 5 ml/100 gm body weight to avoid acute motor effects. In the pharmacological reversal studies, the 5-HT1A antagonist WAY-100635 (0.1, 0.5 mg/kg, i.p.) or the α-1 antagonist prazosin (0.1 mg/kg, i.p.) was co-administered with BMY-14802 30 minutes before L-DOPA. [1]
* **AIM Assessment:** An investigator blinded to the treatment groups rated the severity of limb, axial, and oral AIMs, as well as contraversive rotation. Ratings were performed every 20 minutes for 3 hours, starting 20 minutes after L-DOPA injection, using a scale of 0-4. A total AIM score (limb + axial + oral) was calculated for analysis. [1]

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6-OHDA Lesion Model: Male Sprague-Dawley rats received unilateral infusions of 6-OHDA (22.8 μg/2μl per site) into two sites of the right medial forebrain bundle to model Parkinson's disease. Rats with significant hemi-parkinsonism, defined as an average of ≥5 turns/min over 10 minutes in response to amphetamine (5 mg/kg, i.p.), were selected for the study. [1]
L-DOPA Treatment and AIM Induction: Selected rats were treated once daily for 21 days with L-DOPA methyl ester HCl (7.5 mg/kg, i.p.) combined with benserazide (15 mg/kg, i.p.) and ascorbic acid (2.6 mg/kg, i.p.) to induce stable AIM expression. Following this, they were maintained on a regimen of 2 L-DOPA injections per week. [1]
Drug Testing Protocol: To test the efficacy of BMY-14802 and other compounds on AIM expression, test drugs were administered during the maintenance phase. BMY-14802 (15 mg/kg), buspirone (1, 4, 10 mg/kg), and other sigma agents were dissolved in either milliQ water, 0.9% saline, or β-cyclodextrin solutions. They were administered intraperitoneally (i.p.) at a volume of 1 ml/100 gm body weight, 30 minutes prior to L-DOPA injection. Finasteride was administered 22 hours prior to L-DOPA at a volume of 5 ml/100 gm body weight to avoid acute motor effects. In the pharmacological reversal studies, the 5-HT1A antagonist WAY-100635 (0.1, 0.5 mg/kg, i.p.) or the α-1 antagonist prazosin (0.1 mg/kg, i.p.) was co-administered with BMY-14802 30 minutes before L-DOPA. [1]
AIM Assessment: An investigator blinded to the treatment groups rated the severity of limb, axial, and oral AIMs, as well as contraversive rotation. Ratings were performed every 20 minutes for 3 hours, starting 20 minutes after L-DOPA injection, using a scale of 0-4. A total AIM score (limb + axial + oral) was calculated for analysis. [1]

The pharmacokinetic properties of BMY-14802 have been evaluated in baboons using positron emission tomography (PET) studies. Following intravenous administration of [¹⁸F]-labeled BMY-14802, the compound clears rapidly from plasma, and a glucuronidated metabolite appears. Brain radioactivity peaks at approximately 5 minutes post-injection (0.04-0.07% dose/cc) and then clears rapidly, decreasing to approximately 30% of peak value by 20 minutes and to less than 10% by 60 minutes post-injection in all brain regions. Similar rapid brain clearance is observed in mice. Notably, pretreatment with unlabeled BMY-14802 does not produce the expected reductions in distribution volume and clearance half-times, suggesting that the behavior of BMY-14802 in the brain is dominated by its tissue transport properties rather than its binding to sigma sites.

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According to available safety data sheets, BMY-14802 is classified as a non-hazardous substance or mixture and is not listed as a carcinogen by NTP, IARC, OSHA, or ACGIH. In animal studies, BMY-14802 does not produce stereotyped behavior, ataxia, or seizures at doses ranging from 10-50 mg/kg, suggesting low acute neurotoxicity. As a research-use compound, the toxicological effects of this product have not been thoroughly studied, and it is intended for scientific research use only, not for human therapeutic applications.

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[1]. Synthesis and biological characterization of alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol and analogues as potential atypical antipsychotic agents. J Med Chem. 1992 Nov 27;35(24):4516-25.

[2]. The effects of BMY-14802 against L-DOPA- and dopamine agonist-induced dyskinesia in the hemiparkinsonian rat. Psychopharmacology (Berl). 2013 Jun;227(3):533-44.

[3]. The sigma-1 antagonist BMY-14802 inhibits L-DOPA-induced abnormal involuntary movements by a WAY-100635-sensitive mechanism. Psychopharmacology (Berl). 2009 Jul;204(4):743-54.

See also: Bmy-14802 (Notes moved to).

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BMY-14802 is a compound initially developed as a potential antipsychotic. It is widely used as a sigma-1 antagonist but also has significant agonist activity at serotonin 5-HT1A and adrenergic α-1 receptors. [1]
This study was conducted to determine which of these mechanisms underlies its observed ability to suppress L-DOPA-induced dyskinesia (LID) in a preclinical model. The results demonstrate that its anti-dyskinetic effect is mediated by 5-HT1A receptor agonism, as it is blocked by a 5-HT1A antagonist and replicated by the 5-HT1A agonist buspirone, but not by various sigma agents. [1]
The authors highlight that BMY-14802 is a promising candidate for clinical trials in LID because, unlike some other 5-HT1A agonists that failed clinically (e.g., sarizotan), it has very low affinity for the dopamine D2 receptor (IC50 > 6,430 nM). This low D2 affinity suggests it is unlikely to block the therapeutic effects of L-DOPA or worsen Parkinsonian symptoms. [1]
The study tested and found that several sigma receptor ligands (BD-1047, finasteride, SM-21, DTG, DHEA, carbetapentane, and opipramol) did not suppress AIMs, indicating that sigma receptors are not effective targets for antidyskinesia pharmacotherapy in this model. [1]

C18H23CLF2N4O

384.851229906082

384.153

C, 56.18; H, 6.02; Cl, 9.21; F, 9.87; N, 14.56; O, 4.16

105565-55-7

105565-56-8

3086514

White to off-white solid powder

520.8ºC at 760mmHg

268.8ºC

1.13E-11mmHg at 25°C

3.195

2

7

6

26

379

0

Cl.FC1C=NC(=NC=1)N1CCN(CCCC(C2C=CC(=CC=2)F)O)CC1

NIBVEFRJDFVQLM-UHFFFAOYSA-N

InChI=1S/C18H22F2N4O.ClH/c19-15-5-3-14(4-6-15)17(25)2-1-7-23-8-10-24(11-9-23)18-21-12-16(20)13-22-18;/h3-6,12-13,17,25H,1-2,7-11H2;1H

1-(4-fluorophenyl)-4-[4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]butan-1-ol;hydrochloride

BMS-181100; BMS181100; BMS-181,100; BMS181,100; BMS181,100; BMY-14802; BMY 14802; BMY14802; BMY-14802-1; BMS-181100 HCl; BMS-181100 hydrochloride; BMS181100

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)

DMSO : ~125 mg/mL (~324.80 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (5.40 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 (5.40 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 (5.40 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.)