Sigma 1 Receptor 5-HT1A Receptor α1-adrenergic receptor
5-HT1A receptor (IC50 = 320 nM) [1]
Sigma-1 receptor (IC50 = 112 nM) [1]
Adrenergic α-1 receptor (IC50 = 460 nM) [1]
D2 receptor (IC50 = 6,430 nM) [1]
D1 receptor (IC50 > 1,000 nM) [1]
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.

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.

In rat PD models, BMY 14802 (15 mg/kg; i.p.; single dosage) dramatically inhibits AIM and decreases dyskinesias, particularly in the first hour following therapy [1][2].

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- BMY-14802 (15 mg/kg, i.p.) significantly reduced abnormal involuntary movements (AIMs) over the 3-hour test session in the 6-OHDA rat model of Parkinson's disease, as well as total AIMs during the 3-hour session and in the first hour after L-DOPA administration. This effect was significant for limb, axial, and oral AIM subscales. [1]
- BMY-14802 (15 mg/kg, i.p.) reduced L-DOPA-induced rotational behavior over the 3-hour test session and in the first hour after L-DOPA. [1]
- The AIM-suppressing effect of BMY-14802 (15 mg/kg, i.p.) was dose-dependently prevented by the 5-HT1A antagonist WAY-100635 (0.5 mg/kg, i.p., but not 0.1 mg/kg). [1]
- The adrenergic α-1 antagonist prazosin (0.1 mg/kg, i.p.) did not prevent BMY-14802's (15 mg/kg, i.p.) AIM-suppressing effect. [1]

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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.

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.

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.

- Model Preparation: Male Sprague-Dawley rats (weighing 300g at surgery) received a unilateral 6-hydroxydopamine (6-OHDA) lesion (22.8 μg/2μl of 0.9% saline with 0.02% ascorbic acid, infused at 0.5 μl/min into two sites of the right medial forebrain bundle). Rats selected for the study met an a priori criterion of an average of ≥5 turns/min over ten consecutive minutes in response to amphetamine (5 mg/kg, i.p.). [1]
- L-DOPA Treatment: All rats received L-DOPA methyl ester (7.5 mg/kg, i.p.) combined with benserazide (15 mg/kg, i.p.) and ascorbic acid (2.6 mg/kg, i.p.) once daily for 21 consecutive days to induce AIMs. Thereafter, rats received a maintenance regimen of 2 injections/week. [1]
- Test Drug Administration: Test compounds, including BMY-14802, were administered during the maintenance phase to examine their efficacy to suppress AIM expression. BMY-14802 hydrochloride was dissolved in milliQ water and administered intraperitoneally (i.p.) at 1 ml/100 gm of body weight 30 minutes prior to L-DOPA. The dose used was 15 mg/kg. [1]
- Pharmacological Reversal Study: To determine if BMY-14802's effect is mediated by 5-HT1A or adrenergic α-1 agonism, the 5-HT1A antagonist WAY-100635 (0.1 or 0.5 mg/kg, dissolved in milliQ water, i.p., 30 min prior to L-DOPA) or the adrenergic α-1 antagonist prazosin (0.1 mg/kg, dissolved in milliQ water, i.p., 30 min prior to L-DOPA) was co-administered. [1]
- AIM Assessment: AIM was assessed by an investigator blind to treatment. The severity of limb, axial, and oral AIM was rated on a scale of 0-4 every 20th minute for 3 hours, beginning 20 minutes after L-DOPA. A total AIM score was computed as the sum of limb + axial + oral AIM. [1]

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Six-to-eight-week-old male Sprague-Dawley rats or gerbils are used for in vivo experiments. BMY-14802 is dissolved in saline or appropriate vehicle and administered via intraperitoneal, intravenous, or intragastric routes. For latent inhibition experiments, a conditioned emotional response procedure is employed: the preexposure stage involves repeated presentation of the to-be-conditioned stimulus (e.g., a tone) without reinforcement; the conditioning stage pairs the preexposed stimulus with reinforcement (e.g., foot shock); and the test stage measures the degree of licking suppression as an index of latent inhibition. For cerebral ischemia models, gerbils receive intraperitoneal BMY-14802 (10-50 mg/kg) 30 minutes prior to 5-minute bilateral carotid artery occlusion, followed by reperfusion. Animals are euthanized after 7 days, and hippocampal tissues are collected for histopathological analysis to assess neuronal survival. For microdialysis experiments, probes are implanted into the dorsal raphe or hippocampus, dialysates are continuously collected from awake rats, and neurotransmitter concentrations are analyzed by HPLC-ECD.

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.

- BMY-14802 did not evoke Parkinsonian side effects in clinical trials for schizophrenia. [1]
- BMY-14802 lacks significant D2 antagonism, suggesting it is unlikely to exacerbate Parkinson's disease symptoms. [1]

[1]. 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.

[2]. Sigma ligands, but not N-methyl-D-aspartate antagonists, reduce levodopa-induced dyskinesias. Neuroreport. 2008 Jan 8;19(1):111-5.

- BMY-14802 is a promising candidate for clinical development as an antidyskinesia pharmacotherapy for L-DOPA-induced dyskinesia (LID) in Parkinson's disease patients. [1]
- Unlike other 5-HT1A agonists that have failed clinical trials (e.g., sarizotan) or have submicromolar affinity for the D2 receptor (e.g., buspirone), BMY-14802 is devoid of significant affinity for the D2 receptor. This is an important consideration because an AIM-suppressing agent would be of little use if it counteracted the dopamine-mediated therapeutic effects of L-DOPA. [1]
- The sigma-1 antagonist BMY-14802 has been shown to block the development of behavioral sensitization to methamphetamine. [1]

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1-(4-fluorophenyl)-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]-1-butanol is an N-arylpiperazine.

C18H22F2N4O

348.39

348.176

105565-56-8

108046

White to off-white solid powder

2.393

1

7

6

25

379

0

C1CN(CCN1CCCC(C2=CC=C(C=C2)F)O)C3=NC=C(C=N3)F

ZXUYYZPJUGQHLQ-UHFFFAOYSA-N

InChI=1S/C18H22F2N4O/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

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

Bmy-14802; BMY14802; Bmy 14802; 1-(4-fluorophenyl)-4-[4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]butan-1-ol; A5NB5G07JO; ...; 105565-56-8;

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 mg/mL (143.52 mM)

Solubility in Formulation 1: ≥ 1.67 mg/mL (4.79 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 16.7 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.)