D₂ Receptor ( Ki = 0.06 nM ); D₁ Receptor ( Ki ~350 nM ); D₃ Receptor ( Ki = 0.6 nM ); D₄ Receptor ( Ki = 0.08 nM ); D₅ Receptor ( Ki ~ 3500 nM ); 5-HT_2A Receptor ( Ki = 1 nM ); 5-HT_1A Receptor ( Ki = 49 nM ); α1B-adrenoceptor; Calcium-activated chloride channel

Spiperone is a strong enhancer of intracellular Ca²⁺ (EC50=9.3 μM) that acts on intracellular Ca²⁺ via a pathway dependent on phospholipase C and coupled to protein tyrosine kinase. This causes increased Cl-secretion in Calu-3 and CFBE41o-cell monolayers[2].
Spiperone reduces nitric oxide production in primary astrocyte, primary microglia, and lipopolysaccharide-stimulated BV-2 microglia cells significantly. Additionally, nitric oxide production in primary microglia cultures stimulated with ATP is markedly inhibited by diperone. Spiperone significantly reduces the BV-2 microglia cells' ability to produce TNF-α. In BV-2 microglia cells, siperone reduces the mRNA expression of proinflammatory cytokines like TNF-α and IL-1β as well as inducible nitric oxide synthase[3].

Spiperone (1.5 mg/kg; intraperitoneal injection; on days 1, 3, 6, 7, and 13-21; C57Bl/6 mice) treatment inhibits the growth of connective tissue in the parenchyma of Bleomycin lungs and decreases the infiltration of inflammatory cells into the alveolar ducts and alveolar interstitium[6].

Cystic fibrosis (CF) is caused by mutations in the gene producing the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR functions as a Cl(-) channel. Its dysfunction limits Cl(-) secretion and enhances Na+ absorption, leading to viscous mucus in the airway. Ca2+-activated Cl(-) channels (CaCCs) are coexpressed with CFTR in the airway surface epithelia. Increases in cytosolic Ca(2+) activate the epithelial CaCCs, which provides an alternative Cl(-) secretory pathway in CF. We developed a screening assay and screened a library for compounds that could enhance cytoplasmic Ca2+, activate the CaCC, and increase Cl(-) secretion. We found that spiperone, a known antipsychotic drug, is a potent intracellular Ca2+ enhancer and demonstrated that it stimulates intracellular Ca2+, not by acting in its well-known role as an antagonist of serotonin 5-HT2 or dopamine D2 receptors, but through a protein tyrosine kinase-coupled phospholipase C-dependent pathway. Spiperone activates CaCCs, which stimulates Cl(-) secretion in polarized human non-CF and CF airway epithelial cell monolayers in vitro and in CFTR-knockout mice in vivo. In conclusion, we have identified spiperone as a new therapeutic platform for correction of defective Cl(-) secretion in CF via a pathway independent of CFTR. [2]

---

The structures of ketanserin (1) and spiperone (2) were examined in detail to determine the role of various substituent groups on 5-HT(2A) receptor affinity and selectivity. It was found that the presence of the quinazoline ring of ketanserin detracts from selectivity and that various ring-opened analogs displayed ketanserin-like affinity and up to 30-fold enhanced selectivity. The triazaspirodecanone portion of spiperone is a major determinant of its 5-HT affinity and selectivity. The conformational rigidity imposed by the ring, as well as the nature of the N(1)-substituent, are important factors in controlling binding at 5-HT(2A), 5-HT(2C), 5-HT(1A), and dopamine D2 receptors. Replacement of the N(1)-phenyl ring of spiperone with a methyl group (KML-010; 48) resulted in a compound that binds at 5-HT(2A) receptors with slightly lower affinity than spiperone, but that lacked affinity (Ki >10,000 nM) for 5-HT(2C) and 5-HT(1A) receptors and binds with 400-fold reduced affinity at D2 receptors. [4]

Glial activation and neuroinflammatory processes play an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and HIV dementia. Activated glia cells can secrete various proinflammatory cytokines and neurotoxic mediators, which may influence neuronal cell survival. Recent studies have demonstrated that glia cell-mediated neuroinflammation is also related to the pathophysiology of schizophrenia. In the present study, anti-inflammatory and neuroprotective effects of antipsychotics were investigated using cultured brain cells as a model. The results showed that spiperone significantly decreased the production of nitric oxide in lipopolysaccharide-stimulated BV-2 microglia cells, primary microglia and primary astrocyte cultures. Spiperone also significantly inhibited nitric oxide production in adenosine 5'-triphosphate (ATP)-stimulated primary microglia cultures. Spiperone markedly decreased the production of tumor necrosis factor-alpha in BV-2 microglia cells. Spiperone attenuated the expression of inducible nitric oxide synthase and proinflammatory cytokines such as interleukin-1beta and tumor necrosis factor-alpha at mRNA levels in BV-2 microglia cells. Spiperone inhibited nuclear translocation and DNA binding of the p65 subunit of nuclear factor kappa B (NF-kappaB), inhibitor of kappa B (IkappaB) degradation, and phosphorylation of p38 mitogen-activated protein kinase in the lipopolysaccharide-stimulated BV-2 microglia cells. Moreover, spiperone was neuroprotective, as the drug reduced microglia-mediated neuroblastoma cell death in the microglia/neuron co-culture. These results imply that the antipsychotic spiperone has anti-inflammatory and neuroprotective effects in the central nervous system by modulating glial activation. [3]

C57Bl/6 mice (7-8-week-old) induced pulmonary fibrosis by Bleomycin
1.5 mg/kg
Intraperitoneal injection; on days 1, 3, 6, 7, and 13-21

Oral LD50 in rats >1 g/kg, Japanese Medicine, 6(380), 1982
Intraperitoneal LD50 in rats >500 mg/kg, Pharmacology, 3(390), 1969
Subcutaneous LD50 in rats >50 mg/kg, Pharmacology, 3(390), 1969
Intravenous LD50 in rats 14 mg/kg, Psychotropic Drugs and Related Compounds, 2nd Edition, E. Usdin and DH Efron, Washington, D.C., 1972, -(193), 1972
Intramuscular LD50 in rats 168 mg/kg, Japanese Medicine, 6(380), 1982

[1]. Dopamine receptor pharmacology. Trends Pharmacol Sci. 1994 Jul;15(7):264-70.

[2]. Spiperone, identified through compound screening, activates calcium-dependent chloride secretion in the airway. Am J Physiol Cell Physiol. 2009 Jan;296(1):C131-41.

[3]. The antipsychotic spiperone attenuates inflammatory response in cultured microglia via the reduction of proinflammatory cytokine expression and nitric oxide production. J Neurochem. 2008 Dec;107(5):1225-35.

[4]. Ketanserin and spiperone as templates for novel serotonin 5-HT(2A) antagonists. Curr Top Med Chem. 2002 Jun;2(6):539-58.

[5]. Human umbilical vein vasoconstriction induced by epinephrine acting on alpha1B-adrenoceptor subtype. Am J Obstet Gynecol. 2003 Nov;189(5):1472-80.

[6]. Effect of spiperone on mesenchymal multipotent stromal and hemopoietic stem cells under conditions of pulmonary fibrosis. Bull Exp Biol Med. 2014 May;157(1):132-7.

Objective: This study aimed to determine the presence of α1-adrenergic receptor mRNA subtypes in human umbilical vein (HUV) contraction and to expand the pharmacological characterization of α1-adrenergic receptors involved in this contraction. Study Design: Umbilical cords from 124 healthy women who underwent full-term vaginal delivery or cesarean section were used. Umbilical veins were carefully isolated from the umbilical cords and used for reverse transcription-polymerase chain reaction (RT-PCR) to amplify α1-adrenergic receptor transcripts. HUV loops were immobilized in an ex vivo organ bath, and cumulative concentration-response curves for adrenaline or the selective α1A-adrenergic receptor agonist A-61603 were plotted. In other series of experiments, we evaluated the blocking efficacy of selective α(1A)- and α(1B)-adrenergic receptor antagonists (RS-100329 or B8805-033 or spiroperon, AH11110A, and cyclozosin, respectively) on adrenaline concentration-response curves. Results: α(1a)- and α(1b)-adrenergic receptor transcripts were detected in HUV using RT-PCR. The blocking efficacy of RS-100329 or B8805-033 against the adrenaline-mediated response was inconsistent with the activation of the α(1A)-adrenergic receptor population. Furthermore, the low efficacy of the agonist A-61603 was also inconsistent with α(1A)-adrenergic receptor interactions. On the other hand, the antagonistic efficacy of spiroperon, AH11110A, and cyclozosin was consistent with the interactions of the α(1B)-adrenergic receptor subtypes. Conclusion: Although messenger RNAs of α(1a)- and α(1b)-adrenergic receptors were detected in the human umbilical vein (HUV), only α(1B)-adrenergic receptors were involved in the vasoconstrictive effects of adrenaline. [5]

---

In a C57Bl/6 mouse model of reversible bleomycin-induced pulmonary fibrosis, the antifibrotic properties of spiropyrone and its effects on stem cells and progenitor cells were investigated. Spiopyrone reduced the infiltration of inflammatory cells into the alveolar interstitium and alveolar ducts and inhibited the proliferation of connective tissue in the bleomycin-induced lung parenchyma. In addition to its anti-inflammatory effects, spiropyrone also inhibited bone marrow hematopoietic cells (CD3, CD45R (B220), Ly6C, Ly6G (Gr1), CD11b (Mac1), TER-119), Sca-1+, c-Kit+, CD34- and hematopoietic progenitor cells (granulocyte-erythrocyte-macrophage-megakaryocyte and granulocyte CFU). Spinorphin-induced fibrotic disorder is accompanied by the recovery of lung parenchymal endothelial cells, a decrease in the number of circulating bone marrow cells and lung mesenchymal hematopoietic cells (mesenchymal pluripotent stromal cells (CD31-, CD34-, CD45-, CD44+, CD73+, CD90+, CD106+) and fibroblast progenitor cells), and inhibition of multilineage differentiation of pluripotent mesenchymal stromal cells (including fibroblast lineage cells). [6]

C23H26N3O2F.HCL

431.93078

431.18

C, 63.96; H, 6.30; Cl, 8.21; F, 4.40; N, 9.73; O, 7.41

2022-29-9

Spiperone; 749-02-0

11957687

White to off-white solid powder

2

5

6

30

577

0

QUIKMLCZZMOBLH-UHFFFAOYSA-N

InChI=1S/C23H26FN3O2.ClH/c24-19-10-8-18(9-11-19)21(28)7-4-14-26-15-12-23(13-16-26)22(29)25-17-27(23)20-5-2-1-3-6-20;/h1-3,5-6,8-11H,4,7,12-17H2,(H,25,29);1H

8-[4-(4-fluorophenyl)-4-oxobutyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one;hydrochloride

Spiperone HCl; Spiropitan; Spiperone; Spiperone hydrochloride; 2022-29-9; Spiperone HCl; Spiperone (hydrochloride); DTXSID40873371; 8-[4-(4-fluorophenyl)-4-oxobutyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one;hydrochloride; SR-01000000261; Spiroperidol Hydrochloride; Spiroperidol; Spiroperidone; R-5147; NSC-170983

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 (~289.4 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.82 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.

---

Solubility in Formulation 2: ≥ 2.08 mg/mL (4.82 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.

---

View More

Solubility in Formulation 3: ≥ 2.08 mg/mL (4.82 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.

---

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