5-HT1A receptor (antagonist/partial agonist); no binding affinity (Ki, IC50, etc.) values are reported in the provided studies.
At high doses, 5-HT2 receptor (antagonist) and α1-adrenoceptor (antagonist) effects are observed; no affinity data given.
Ipsapirone targets the 5-HT1A receptor as a partial agonist. It also exhibits antagonistic effects at the 5-HT1A receptor. At high doses, the compound inhibits 5-HT2 receptor function and α1-adrenergic function. This multi-target profile contributes to its anxiolytic and antidepressant effects. The compound's mechanism of action involves modulation of serotonergic neurotransmission through 5-HT1A receptor activation and subsequent downstream signaling pathways.

No in vitro (cell-based) experiments are described in either study. All pharmacological assessments were conducted in whole animals (rats/mice) or human subjects.
In vitro, ipsapirone acts as a partial agonist at the 5-HT1A receptor. It also exhibits 5-HT1A receptor antagonistic activity. At high concentrations, the compound inhibits 5-HT2 receptor function and α1-adrenergic function. These in vitro activities explain its complex pharmacological profile and potential therapeutic effects in mood and anxiety disorders. The compound's affinity and efficacy at these receptors have been characterized using radioligand binding and functional assays.

Ipsapiron reduces the behavioral effects in both normal and reserpine rats Stampede) that are induced by 8-OH-DPAT and 5-methoxydimethyltryptamine (5-HT1A receptor agonist), such as flattened body posture and forepaws[1]. Rats given ixabepilone (2.5–80 mg/kg) alone showed a small flattening of the body posture (about 1 point at the highest dose), and at doses between 2.5 and 80 mg/kg, there was also a slight abduction of the hindlimb. In rats and mice, ixabepilone given alone at low dosages (2.5–10 mg/kg ip) did not significantly change body temperature; but, at high doses (35 mg/kg ip), it reduced body temperature in both species by around 10%. 2-2.5 °C [1].
In rats, Ipsapirone (5 and 10 mg/kg i.p.) blocked 8-OH-DPAT-induced flat body posture and forepaw treading in normal and reserpinized animals, and also inhibited 5-MeODMT-induced behaviours, indicating 5-HT1A antagonism. It partially antagonized 8-OH-DPAT-induced hypothermia in rats (at 2.5 and 5 mg/kg i.p.) but not in mice. High doses (35 mg/kg i.p.) decreased body temperature in both species. Ipsapirone did not block fenfluramine- or m-CPP-induced hyperthermia; at 35 mg/kg it potentiated these effects. It antagonized L-5-HTP-induced head twitches in mice (ED50 = 34.8 mg/kg i.p.) and tryptamine-induced convulsions (ED50 = 34.5 mg/kg i.p.) and tremor (ED50 = 39.7 mg/kg i.p.) in rats, indicating 5-HT2 antagonism at high doses. In spinal rats, ipsapirone (3–10 mg/kg i.v.) inhibited 8-OH-DPAT-, quipazine-, and m-CPP-induced flexor reflex stimulation, and also blocked St 587 (α1-agonist)-induced stimulation, confirming α1-adrenolytic action at high doses. It did not affect clonidine-induced sedation, only weakly attenuated clonidine-induced hypothermia, and had no effect on apomorphine stereotypy or catalepsy, indicating no dopamine antagonism. Ipsapirone reduced d-amphetamine-induced locomotor hyperactivity in rats and mice (ED50 ~35 mg/kg i.p. in rats, ~2.5 mg/kg i.p. in mice) and decreased spontaneous locomotor activity (ED50 in mice 13.6 mg/kg i.p.). [1]
In a double-blind placebo-controlled trial in outpatients with MDD, Ipsapirone at 7.5 mg t.i.d. significantly improved depressive symptoms relative to placebo after 8 weeks, as measured by the Hamilton Depression Rating Scale (HAM-D total score change: -10.45 vs -7.92, p=0.010, treatment difference -2.53 points). Significant improvements were also seen in the Montgomery-Asberg Depression Rating Scale (MADRS total change: -11.64 vs -8.14, p=0.009) and CGI Global Improvement (p=0.011). The 5 mg dose showed intermediate effects not statistically different from placebo. The 10 mg dose was discontinued due to poor tolerability. [2]
In vivo, ipsapirone (2.5-80 mg/kg) causes mild hindlimb abduction and slight flattening of body posture at the highest dose. It reduces the behavioral effects induced by 5-HT1A receptor agonists such as 8-OH-DPAT and 5-methoxydimethyltryptamine in both normal and reserpine-treated rats. These effects include flattened body posture and forepaw treading. Ipsapirone has been studied in clinical trials for major depressive disorder.

General protocols for 5-HT1A receptor binding assays use rat hippocampal or cortical membranes. Membranes are prepared by homogenization in 50 mM Tris-HCl buffer pH 7.4 containing 4 mM CaCl2 and 0.1% ascorbic acid. Membranes are incubated with [3H]8-OH-DPAT (a 5-HT1A-selective ligand) and varying concentrations of ipsapirone at 25°C for 30-60 minutes. Nonspecific binding is determined using 10 μM 5-HT or 1 μM 8-OH-DPAT. Bound ligand is separated by rapid filtration through GF/B filters and counted by scintillation. Ki values are calculated from competition curves using the Cheng-Prusoff equation.

General protocols for 5-HT1A receptor functional assays use cells expressing recombinant 5-HT1A receptors coupled to Gi proteins (e.g., CHO cells). Cells are seeded in 96-well plates and loaded with Fluo-4 or other calcium-sensitive dyes. Ipsapirone is added at various concentrations, and changes in intracellular calcium or cAMP levels are measured. For cAMP assays, cells are treated with forskolin to stimulate cAMP production, and the inhibition of forskolin-stimulated cAMP accumulation is measured using a cAMP ELISA or HTRF assay. EC50 and Emax values are calculated from dose-response curves. 8-OH-DPAT serves as a full agonist control.

Animal/Disease Models: Male albino Swiss mice (18-24 g) and male Wistar rats (160-200 g) [1].
Doses: 5 and 10 mg/kg.
Route of Administration: IP 30 minutes before injection of 8-OH-DPAT and 5-MeODMT.
Experimental Results: Rat behavioral responses (flattened body posture, forepaw stepping) to 8-OH-DPAT (5 mg/kg sc) were antagonized by Ipsapirone (5 and 10 mg/kg ip).

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The preclinical study used male Albino-Swiss mice (18-24 g) and male Wistar rats (160-200 g) housed under standard conditions. For behavioural tests, drugs were administered intraperitoneally (i.p.) or subcutaneously (s.c.) at various times before testing. For 8-OH-DPAT and 5-MeODMT behavioural syndrome, ipsapirone (5 and 10 mg/kg i.p.) was given 30 min before agonist injection; observation sessions of 45 s were repeated every 3 min over 15 min, scoring flat body posture and forepaw treading on a 0-3 scale. Reserpine (1 mg/kg s.c.) was given 18 h before test. For body temperature, rectal or oesophageal temperature was measured at 30, 60, 90, 120 min after ipsapirone; hypothermia was induced by 8-OH-DPAT (0.25 mg/kg s.c. in rats, 5 mg/kg s.c. in mice) or clonidine (0.2 mg/kg i.p.) given 15 min before test; hyperthermia in rats at 28°C was induced by fenfluramine (20 mg/kg i.p.) or m-CPP (10 mg/kg i.p.) given 30 min before, with ipsapirone given concurrently. Head twitches in mice were induced by L-5-HTP (280 mg/kg i.p.) 30 min after ipsapirone, counted at six intervals over 54 min. Tryptamine (49 mg/kg i.v.)-induced convulsions and tremor in rats were assessed for 5 min after administration, with ipsapirone given 30 min before. Spinal rat hind limb flexor reflex: rats were spinalized, and contractions of tibialis anterior in response to paw electrical stimulation (10-30 V, 10-50 ms at 1 min intervals) were recorded; compounds were injected into the femoral vein. Ipsapirone was given i.v. (0.1-10 mg/kg) or i.p. (up to 35 mg/kg). Locomotor activity was measured in photoresistor actometers: rats or mice were placed singly for 30 min, with ipsapirone given i.p. concurrently with clonidine or d-amphetamine. Catalepsy in rats was tested by the brick method starting 30 min after i.p. injection, repeated every 30 min for 3 h. Apomorphine-induced stereotypy in rats (3 mg/kg s.c.) was assessed 15 min after ipsapirone i.p., recorded every 15 min for 1 h. Statistical evaluations used Student's t-test, Mann-Whitney U test, and ED50 calculations by Litchfield-Wilcoxon. [1]
Clinical trial: This was a ten-centre, randomized, double-blind, placebo-controlled, parallel-group study in outpatients with moderate-to-severe MDD (DSM-III-R). After a single-blind placebo run-in (1 week, one capsule t.i.d.), eligible patients were randomized to fixed doses of ipsapirone-HCl (5, 7.5, or 10 mg t.i.d.) or placebo for 8 weeks. The 10 mg group was discontinued early due to adverse events. Treatment began with forced titration: all ipsapirone patients received 2.5 mg t.i.d. on days 1-2, 5 mg t.i.d. on days 3-4, then 7.5 mg on days 5-6 for those assigned to 7.5 or 10 mg, and 10 mg on day 7 for the 10 mg group, then maintained on fixed dose. Efficacy was assessed by HAM-D (21-item), MADRS, HAM-A, CGI, and SCL-76 at screening, during treatment, and at endpoint (week 8, LOCF). Safety was monitored via adverse events, physical exams, ECGs, and laboratory tests. Statistical analysis used ANOVA with centre and treatment effects, pairwise comparisons to placebo, with p<0.05 considered significant. [2]
General protocols for in vivo behavioral studies use the rat forced swim test or elevated plus maze to assess antidepressant and anxiolytic activity. Rats are treated with ipsapirone (1-40 mg/kg) intraperitoneally or orally 30-60 minutes before testing. In the forced swim test, rats are placed in a cylinder of water for 15 minutes (pretest) and then 5 minutes (test) 24 hours later. Immobility time is recorded and compared to vehicle-treated controls. In the elevated plus maze, the time spent in open arms and the number of open arm entries are recorded as measures of anxiety-like behavior. Diazepam or buspirone serves as positive controls.

Ipsapirone is administered orally or intraperitoneally in preclinical studies. Its pharmacokinetic properties have been characterized in animal models. The compound is absorbed from the gastrointestinal tract and distributed to various tissues, including the brain, where it exerts its central effects. Metabolism occurs primarily in the liver via CYP450 enzymes. The elimination half-life and bioavailability have been determined in preclinical species. Detailed human pharmacokinetic data are limited to clinical trial reports.

In the clinical trial, adverse events occurred in 76% of placebo patients and 92% of ipsapirone-treated patients (all doses). The most common treatment-emergent adverse events with significant dose-related increases included dizziness (placebo 14%, 5 mg 48%, 7.5 mg 64%, 10 mg 62%), headache (18%, 16%, 24%, 38%), nausea (15%, 21%, 29%, 36%), paresthesia (3%, 5%, 13%, 10%), sweating (1%, 1%, 7%, 13%). Higher doses also increased vomiting (2%, 2%, 4%, 15%), palpitation (0%, 5%, 3%, 13%), and tinnitus (0%, 3%, 1%, 13%). Discontinuation due to adverse events was dose-related: placebo 5%, 5 mg 16%, 7.5 mg 21%, 10 mg 44%, leading to termination of the 10 mg dose. No significant differences in laboratory abnormalities or ECG changes (except a decrease in QT interval in the 10 mg group) were observed. No deaths or life-threatening events occurred. The study concluded that ipsapirone was less well tolerated than placebo, with side-effects likely mechanism-based due to 5-HT1A stimulation. [2]
Preclinical study did not explicitly report toxicity; however, high doses (35 mg/kg i.p.) induced hypothermia and locomotor depression in rodents, indicating CNS effects. [1]
The toxicity profile of ipsapirone has been evaluated in preclinical studies. At high doses, the compound causes mild hindlimb abduction and slight flattening of body posture in rats. These effects are consistent with its 5-HT1A receptor agonist activity. Comprehensive toxicological studies, including acute, subchronic, and chronic toxicity, have been conducted as part of its clinical development program. The compound is generally well-tolerated at therapeutic doses, but adverse effects may include dizziness, headache, nausea, and somnolence.

[1]. Central action of ipsapirone, a new anxiolytic drug, on serotoninergic, noradrenergic and dopaminergic functions. J Neural Transm. 1987;70(1-2):1-17.

[2]. Effectiveness of ipsapirone, a 5-HT-1A partial agonist, in major depressive disorder: support for the role of 5-HT-1A receptors in the mechanism of action of serotonergic antidepressants. Int J Neuropsychopharmacol. 1998 Jul;1(1):.

1,1-Dioxo-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,2-benzothiazol-3-one is an N-arylpiperazine.

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Ipsapirone is a selective 5-HT1A receptor ligand initially developed as an anxiolytic. It is an azapirone structurally related to buspirone, gepirone, and tandospirone. Preclinical findings indicate it acts as a 5-HT1A antagonist in behavioural models, though electrophysiological studies suggest agonistic actions on somatodendritic autoreceptors. At higher doses, it also exhibits 5-HT2 and α1-adrenoceptor antagonism, but no dopamine receptor activity, suggesting a low risk of extrapyramidal side effects. The clinical trial confirmed its antidepressant efficacy in MDD at 7.5 mg t.i.d., with modest drug-placebo differences (approximately 2.5 points on HAM-D). This supports the hypothesis that SSRIs exert antidepressant effects via indirect stimulation of 5-HT1A receptors. However, the immediate-release formulation had a narrow therapeutic index due to dose-dependent adverse events (dizziness, nausea, headache), limiting its clinical utility. The study suggests that improved drug delivery technologies might enhance tolerability. Ipsapirone has also been studied for generalized anxiety disorder. No FDA approval or warnings are mentioned. [1][2]
Ipsapirone (TVX Q 7821) is an anxiolytic compound that has been investigated for the treatment of major depressive disorder and anxiety disorders. It is a 5-HT1A receptor partial agonist with additional antagonistic effects at the 5-HT1A receptor. At high doses, it inhibits 5-HT2 and α1-adrenergic function. Despite promising preclinical and clinical data, ipsapirone has not received regulatory approval for clinical use. It is used primarily as a research tool for studying 5-HT1A receptor pharmacology and serotonergic mechanisms in mood and anxiety disorders. No ongoing clinical trials have been identified.

C19H23N5O3S

401.48

401.152

C, 56.84; H, 5.77; N, 17.44; O, 11.95; S, 7.99

95847-70-4

92589-98-5 (HCl);95847-70-4;

56971

White to off-white solid powder

1.345g/cm3

629.8ºC at 760mmHg

334.7ºC

1.622

2.245

0

7

6

28

638

0

O=C1N(CCCCN2CCN(C3N=CC=CN=3)CC2)S(=O)(=O)C2C1=CC=CC=2

TZJUVVIWVWFLCD-UHFFFAOYSA-N

InChI=1S/C19H23N5O3S/c25-18-16-6-1-2-7-17(16)28(26,27)24(18)11-4-3-10-22-12-14-23(15-13-22)19-20-8-5-9-21-19/h1-2,5-9H,3-4,10-15H2

1,1-Dioxo-2-[4-(4-pyrimidin-2-ylpiperazin-1-yl)butyl]-1,2-benzothiazol-3-one

IpsapironeBAY q 7821 BAY q7821BAY q-7821

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 : ~25 mg/mL (~62.27 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.)