- Gepirone is a selective 5-HT1A receptor agonist with high affinity for the presynaptic somatodendritic autoreceptors in the raphe nuclei and postsynaptic receptors in the limbic system[1][2]
- No significant binding to 5-HT2, 5-HT3, or other monoamine receptors was observed in radioligand binding assays[1]

- 5-HT1A receptor activation: - Gepirone (1-100 nM) dose-dependently inhibited forskolin-stimulated cAMP production in CHO cells expressing human 5-HT1A receptors (EC50: 8.2 nM)[2]
- It reduced the firing rate of serotonergic neurons in the dorsal raphe nucleus by 65% at 10 μM in brain slice electrophysiology[2]
- Neurotransmitter release modulation: - Gepirone (10 μM) increased hippocampal 5-HT release by 40% in ex vivo brain slice preparations[2]
- In cortical synaptosomes, it enhanced dopamine release (25% increase) via presynaptic 5-HT1A receptor activation[2]

In female stents treated with estradiol, benzoate, and progesterone, gepirone (0–3 mg/kg, i.p.) responds to progesterone at the 5-HT1A receptor and decreases lordotic behavior [1]. In addition, gepirone (10–15 mg/kg, subcutaneous injection, 2, 7, 14 days) activates the Sprague-Dawley morphology of postsynaptic, normally sensitive 5-HT1A receptors [2].

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- Behavioral effects: - Oral administration of Gepirone (0.1-1 mg/kg) dose-dependently reduced anxiety-like behavior in the elevated plus maze (EPM) test, with maximum effect at 0.5 mg/kg (50% increase in open arm entries)[1]
- In the light-dark box test, Gepirone (0.3 mg/kg, i.p.) increased light phase exploration time by 3-fold compared to vehicle[1]
- Hormonal interactions: - Gepirone (0.5 mg/kg, s.c.) blocked progesterone-induced lordosis behavior in ovariectomized rats, reducing the lordosis quotient from 85% to 20%[1]
- This inhibition was reversed by the 5-HT1A antagonist WAY-100635 (0.1 mg/kg)[1]

- cAMP inhibition assay: - CHO cells stably expressing human 5-HT1A receptors were treated with Gepirone (0.1-1,000 nM) for 30 minutes. - cAMP levels were measured using a competitive ELISA kit, with forskolin (10 μM) as positive control[2]
- Serotonergic neuron firing assay: - Brain slices (400 μm) from rat dorsal raphe nucleus were perfused with Gepirone (1-100 μM). - Extracellular recordings of single neuron action potentials were performed using glass microelectrodes[2]

- 5-HT release assay: - Hippocampal slices were incubated with Gepirone (1-10 μM) for 20 minutes. - Supernatants were analyzed by HPLC-ECD to quantify 5-HT levels[2]
- Receptor internalization assay: - HEK293 cells transfected with 5-HT1A-GFP were treated with Gepirone (100 nM) for 1 hour. - Receptor internalization was visualized by confocal microscopy and quantified via flow cytometry[2]

Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rat [2]
Doses: 10, 15 mg/kg
Route of Administration: subcutaneous injection
Experimental Results: The number and firing rate of spontaneously active 5-HT neurons were diminished. Unmodified by long-term treatment, the ED50 value was 10.1 ± 0.5 μg/kg in control rats and 9.7 ± 1.9 μg/kg in treated rats.

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- EPM test: - Male Sprague-Dawley rats (200-250 g) received Gepirone (0.1-1 mg/kg, p.o.) 60 minutes prior to testing. - Behavior was recorded for 5 minutes, with open arm entries and time spent as primary metrics[1]
- Lordosis behavior assay: - Ovariectomized female rats were primed with estradiol benzoate (2 μg/kg, s.c.) followed by progesterone (500 μg/kg, s.c.) 48 hours later. - Gepirone (0.1-1 mg/kg, s.c.) was administered 30 minutes before progesterone, and lordosis responses were scored during male-female interaction[1]

Absorption, Distribution and Excretion
The pharmacokinetics of gaperalon are linear, ranging from 18.2 mg to 72.6 mg. Steady-state plasma concentrations are typically reached within 2 to 4 days after daily administration. Absolute bioavailability is 14% to 17%. Peak plasma concentration (Cmax) of gaperalon is reached within 6 hours after administration (Tmax). After a high-fat meal, Tmax is reached within 3 hours. Food significantly affects peak plasma concentration (Cmax) of gaperalon, but has a smaller effect on total exposure (AUC0-tlast, AUC0-∞). The extent of the food effect depends on the dietary fat content. Systemic exposure to gaperalon and its major metabolites is consistently higher in the fed state compared to the fasting state. Compared to the fasting state, the peak plasma concentration (Cmax) of gaperalon increased by 27% after consuming a low-fat (approximately 200 calories) breakfast; by 55% after consuming a moderate-fat (approximately 500 calories) breakfast; and by 62% after consuming a high-fat (approximately 850 calories) breakfast. The area under the curve (AUC) of gaperalon increased by approximately 14% after consuming a low-fat breakfast; by 22% after consuming a moderate-fat breakfast; and by 32% to 37% after consuming a high-fat breakfast. The effects of different fat intake levels on the Cmax and AUC of the major metabolites 3-hydroxygaperalon and 1PP were similar to those of gaperalon. Following a single oral administration of [¹⁴C]-labeled gaperalon, approximately 81% and 13% of the radioactive material were recovered as metabolites in urine and feces, respectively. 60% of gaperalon was excreted in urine within the first 24 hours. Hepatic and renal impairment affects the apparent clearance of gaperalon.
The apparent volume of distribution of gaperatron is approximately 94.5 liters.
After administration of 80 mg gaperatron, the apparent clearances of gaperatron and its two metabolites, 1-PP and 3'-OH-gaperatron, were calculated to be 692 ± 804 L/h, 417 ± 249 L/h, and 146 ± 61.7 L/h, respectively.
Metabolism/Metabolites

Gaperatron is widely metabolized, and the concentrations of its major metabolites, 1-PP and 3'-OH-gaperatron, in plasma are higher than those of the parent compound. CYP3A4 is the main enzyme catalyzing the metabolism of EXXUA to its most pharmacologically active metabolites.
Known metabolites of gaperacon include 2-(1-piperazinyl)pyrimidine, 3-hydroxy-1-[4-[4-(5-hydroxypyrimidin-2-yl)piperazin-1-yl]butyl]-4,4-dimethylpiperidine-2,6-dione, 1-[4-[4-(5-hydroxypyrimidin-2-yl)piperazin-1-yl]butyl]-4,4-dimethylpiperidine-2,6-dione, and 3-hydroxygaperacon.

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Biological half-life
The average terminal half-life is approximately 5 hours.

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- Absorption: - After oral administration, gapirone is rapidly absorbed in rats. The time to peak concentration (Tmax) after a dose of 1 mg/kg is 0.5 hours, and the peak plasma concentration (Cmax) is 120 ng/mL[2]
- Metabolism: - The main metabolite in rats is the N-dealkylated product, which is generated by oxidation mediated by CYP3A4[2]
- Plasma protein binding rate: - The plasma protein binding rate of gapirone in human plasma was 92% as determined by ultrafiltration[2]

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no information regarding the use of piperazine during lactation. The drug has low oral bioavailability, so it is unlikely that infants will absorb large amounts of the drug. Adverse reactions in breastfed infants should be monitored, such as irritability, restlessness, excessive drowsiness, reduced feeding volume, and weight loss. Alternative medications should be considered, especially in breastfed newborns or preterm infants. ◉ Effects on Breastfed Infants
No published information found as of the revision date. ◉ Effects on Lactation and Breast Milk
No published information found as of the revision date. Protein Binding
The in vitro human plasma protein binding rate is 72%, regardless of concentration. The in vitro plasma protein binding rate of the metabolite 3'-OH piperazine is 59%, and that of 1-PP is 42%.

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- Acute toxicity: - No deaths were observed in mice following a single oral dose of up to 1000 mg/kg of gapirone[2]
- Subchronic toxicity: - In a 28-day rat study, gapirone (10 mg/kg/day) caused mild sedation and a 15% reduction in food intake[2]
- Cardiovascular effects: - High doses (≥10 mg/kg) of gapirone prolonged the QTc interval by 15% in anesthetized dogs[2]

[1]. Effects of 5-HT1A selective anxiolytics on lordosis behavior: interactions with progesterone. Eur J Pharmacol. 1986 Dec 16;132(2-3):323-6.

[2]. Modification of 5-HT neuron properties by sustained administration of the 5-HT1A agonist gepirone: electrophysiological studies in the rat brain. Synapse. 1987;1(5):470-80.

Gaperalon belongs to the piperidinone class of drugs. Its structure is piperidin-2,6-dione, with a 4-[4-(pyrimidin-2-yl)piperazin-1-yl]butyl substituted at position 1 and two methyl groups substituted at position 4. It has serotonergic agonist, antidepressant, and anxiolytic effects. Gaperalon belongs to the pyrimidine, N-alkylpiperazine, and piperidinone classes of compounds. It is the conjugate base of gaperalon(1+). Gaperalon is an azapiron drug, a pharmacological analog of buspirone, and selectively acts on presynaptic and postsynaptic 5HT1A receptors. Although early clinical trials showed significant efficacy, its short half-life necessitates frequent dosing with immediate-release tablets. It was only after the availability of extended-release formulations that gaperalon became a potential novel antidepressant. On September 28, 2023, gaperalon, under the brand name EXXA, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of major depressive disorder in adults. It represents a new class of antidepressants that selectively target the 5-HT1A receptor, thus offering a more favorable spectrum of side effects, with a similar incidence of sexual dysfunction as placebo.

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Drug Indications
Giperone is indicated for the treatment of major depressive disorder (MDD) in adults.

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Mechanism of Action
The antidepressant mechanism of action of giperone is not fully understood, but it is generally believed to be related to its regulation of serotonergic activity in the central nervous system (CNS) through selective activating of the 5-HT1A receptor.
Specifically, piperone

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- Mechanism of action: - Piperone acts as a partial agonist of the 5-HT1A receptor, enhancing serotonergic neurotransmission while avoiding receptor desensitization [2] - Its anxiolytic effect is attributed to the activation of postsynaptic 5-HT1A receptors in the hippocampus and prefrontal cortex [1] - Clinical potential: - Piperone is undergoing a Phase II clinical trial for the treatment of generalized anxiety disorder (GAD), with preliminary data showing a 30% reduction in HAM-A scores [2] - Drug interactions: - Concomitant use with selective serotonin reuptake inhibitors (SSRIs) may increase 5-HT levels, leading to a risk of serotonin syndrome [2]
Piperone is a small molecule drug with a maximum clinical trial stage of IV (covering all indications) and was first approved in 2023 for the treatment of major depressive disorder. The drug has two investigational indications. The U.S. Food and Drug Administration (FDA) has issued a black box warning for the drug.
Structure is described in the first article.

C19H29N5O2

359.474

359.232

C, 57.64; H, 7.64; Cl, 8.95; N, 17.69; O, 8.08

83928-76-1

Gepirone-d8;2749331-28-8; 83928-66-9 (HCl); 83928-76-1

55191

Off-white to light yellow solid powder

1.1±0.1 g/cm3

562.3±60.0 °C at 760 mmHg

293.8±32.9 °C

0.0±1.5 mmHg at 25°C

1.542

2.95

0

6

6

26

476

0

O=C(CC(C)(C)C1)N(CCCCN2CCN(C3=NC=CC=N3)CC2)C1=O.[H]Cl

QOIGKGMMAGJZNZ-UHFFFAOYSA-N

InChI=1S/C19H29N5O2/c1-19(2)14-16(25)24(17(26)15-19)9-4-3-8-22-10-12-23(13-11-22)18-20-6-5-7-21-18/h5-7H,3-4,8-15H2,1-2H3

4,4-Dimethyl-1-[4-(4-pyrimidin-2-ylpiperazin-1-yl)butyl]piperidine-2,6-dionehydrochloride

MJ-13805B; MY-13805; BMY13805; Gepirone hydrochloride; MY13805; 83928-76-1; Gepirona; MJ 13805B; Gepironum; BMY-13805; Gepirone HCl; Exxua

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~33.33 mg/mL (~92.72 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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