5-HT₁A receptor (Ki = 27 ± 5 nM)
5-HT₂ receptor (Ki = 1300 ± 200 nM)
5-HT₁C receptor (Ki = 2600 ± 60 nM)
α₁-adrenergic receptor (Ki = 1600 ± 80 nM)
α₂-adrenergic receptor (Ki = 1900 ± 400 nM)
Dopamine D₂ receptor (Ki = 1700 ± 300 nM)
Dopamine D₁ receptor (Ki = 41,000 ± 10,000 nM)
5-HT₁B receptor (Ki > 100,000 nM)
5-HT₁D receptor (Ki > 100,000 nM)
5-HT uptake site (Ki > 100,000 nM)
β-adrenergic receptor (Ki > 100,000 nM)
Muscarinic cholinergic receptor (Ki > 100,000 nM)
Benzodiazepine receptor (Ki > 100,000 nM)[1]
5-HT-1A receptor (Ki = 2.1 × 10⁻⁸ M for unlabeled Tandospirone citrate (SM-3997) displacing ³H-8-OH-DPAT)[2]
5-HT_1A receptor partial agonist [3]

- In radioligand binding assays using rat and pig brain homogenates, Tandospirone displayed highest affinity for the 5-HT₁A receptor with a Ki value of 27 ± 5 nM. Its affinity for other receptors (5-HT₂, 5-HT₁C, α₁, α₂, dopamine D₁ and D₂) was approximately two to three orders of magnitude lower (Ki values ranging from 1300 to 41000 nM). Tandospirone was essentially inactive (Ki > 100,000 nM) at 5-HT₁B, 5-HT₁D, 5-HT uptake sites, β-adrenergic, muscarinic cholinergic, and benzodiazepine receptors. [1]
- Saturation binding studies using [³H]-Tandospirone in rat cortical membranes demonstrated specific, saturable, and high-affinity binding to a homogeneous population of sites, with a K_D of 4.5 ± 0.8 nM and a B_max of 2.2 ± 0.6 pmol/g tissue. [1]
- In competition binding studies, [³H]-Tandospirone binding was potently displaced by known 5-HT₁A agents: 8-OH-DPAT (Ki = 0.34 ± 0.1 nM), 5-HT (Ki = 0.61 ± 0.1 nM), ipsapirone (Ki = 1.1 ± 0.3 nM), buspirone (Ki = 5.6 ± 0.1 nM), Tandospirone itself (Ki = 7.6 ± 2.0 nM), and gepirone (Ki = 80 ± 20 nM). Its metabolite, 1-PP, showed much weaker affinity (Ki = 540 ± 20 nM). [1]
- In adenylate cyclase assays using rat hippocampal membranes, forskolin (10⁻⁵ M) stimulated basal activity approximately 8-fold. The selective 5-HT₁A agonist 8-OH-DPAT (at concentrations ≥ 10⁻⁸ M) inhibited this forskolin-stimulated activity by a maximum of 38% ± 8%. Tandospirone (10⁻⁵ M) partially inhibited the stimulated activity by 23% ± 5%, displaying approximately 60% of the agonist effect of 8-OH-DPAT, indicating it acts as a partial agonist at the 5-HT₁A receptor. [1]
³H-Tandospirone citrate (SM-3997) binds rapidly, reversibly, saturably, and with high affinity to a single population of sites in rat brain hippocampal membranes. The equilibrium dissociation constant (Kd) is 9.4 nM, and the maximum binding capacity (Bmax) is 213 fmol/mg protein. The binding is monophasic with a Hill coefficient of 1.04. Specific binding is approximately 90% of total binding.[2]
The specific binding of ³H-Tandospirone citrate (SM-3997) is completely displaced by serotonin (5-HT) and related compounds. Among tested agents, the 5-HT-1A selective agonist 8-OH-DPAT shows the highest affinity (Ki = 1.4 × 10⁻⁹ M) for these binding sites. The binding profile (Ki values for various neurotransmitters, drugs like TFMPP, cyproheptadine, pindolol) is very similar to that of ³H-8-OH-DPAT binding to 5-HT-1A receptors.[2]
Binding is inhibited by EDTA (5 mM) and physiological concentrations of Na⁺ (120 mM). It is enhanced by divalent cations Mg²⁺ (1 mM), Ca²⁺ (2 mM), and particularly Mn²⁺ (1 mM).[2]
GTP (0.1 mM) and its non-hydrolyzable analog GppNHp significantly reduce ³H-Tandospirone citrate (SM-3997) binding (to 49.5% and 41.7% of control, respectively) by decreasing the affinity (increasing Kd to 24.7 nM) without changing the Bmax, while ATP and GMP have no notable effect.[2]
The regional distribution of specific ³H-Tandospirone citrate (SM-3997) binding sites in rat brain is: hippocampus >> cerebral cortex > thalamus > mesencephalon > hypothalamus > striatum > pons & medulla oblongata >> cerebellum, which closely matches the distribution of ³H-8-OH-DPAT (5-HT-1A) binding sites but differs from that of ³H-5-HT binding sites.[2]

Acute intraperitoneal administration of Tandospirone citrate (SM-3997) (0.1 and 1 mg/kg) significantly decreased the number of premature responses in a dose-dependent manner in the 3-choice serial reaction time task (3-CSRTT) in rats, which is an index of impulsive-like action. This effect was selective, as it did not significantly affect accuracy (attention), omissions, perseverative responses, or correct response latency. The effect was not due to reduced appetite, as a separate food consumption test showed no significant anorexic effect at 1 mg/kg.
The suppressing effect of Tandospirone citrate (SM-3997) (1 mg/kg) on impulsive action was not reversed by pre-treatment with the selective 5-HT_1A receptor antagonist WAY100635 (0.3 mg/kg, s.c.). Instead, co-administration of Tandospirone citrate (SM-3997) and WAY100635 prolonged reward latency. Furthermore, a higher dose of WAY100635 (1 mg/kg, s.c.) alone also suppressed impulsive action. These results suggest that the anti-impulsive effect of Tandospirone citrate (SM-3997) might be due to antagonistic, rather than agonistic, action at 5-HT_1A receptors under the experimental conditions.[3]

Adenylate cyclase activity was determined in rat hippocampal membrane homogenates to assess functional activity at the 5-HT₁A receptor. The assay measured the conversion of [α-³²P]ATP to [³²P]cyclic AMP (cAMP). The reaction mixture contained Tris-HCl buffer, ATP, magnesium acetate, GTP, pargyline, ascorbate, theophylline, cAMP, creatine phosphokinase, creatine phosphate, [α-³²P]ATP, sucrose, EGTA, Na₂EDTA, dithiothreitol, and various drug concentrations. The mixture was incubated with hippocampal membrane preparation. The reaction was stopped, and labeled cAMP was isolated by sequential chromatography on Dowex 50 cation exchanger and neutral alumina. Activity was expressed as pmol cAMP/min/mg protein. Forskolin was used to stimulate cyclase activity, and the inhibitory effects of 8-OH-DPAT and Tandospirone were tested. [1]
The study employed a radioligand binding assay to characterize the binding of ³H-Tandospirone citrate (SM-3997) to rat brain membranes. Rat brain regions (e.g., hippocampus) were homogenized in ice-cold Tris-HCl buffer (pH 7.4). The homogenate was centrifuged, and the pellet was washed, resuspended, and incubated at 37°C to remove endogenous 5-HT. The final membrane pellet was resuspended in Tris-HCl buffer. For saturation binding, membranes (0.5 mg protein/ml) were incubated with increasing concentrations of ³H-Tandospirone citrate (SM-3997) (0.1 - 32 nM) at 25°C for 30 min in Tris-HCl buffer. For competition binding, a fixed concentration of ³H-ligand was incubated with varying concentrations of unlabeled competing drugs. Non-specific binding was defined in the presence of 10 µM unlabeled Tandospirone citrate (SM-3997), 8-OH-DPAT, or 5-HT. Incubations were terminated by rapid vacuum filtration through glass fiber filters, followed by washing with ice-cold buffer. Bound radioactivity on the filters was quantified by liquid scintillation counting. For modulation studies, assays were conducted in the presence of added cations (e.g., Na⁺, Mg²⁺, Ca²⁺, Mn²⁺), EDTA, or nucleotides (GTP, ATP, GMP). Binding parameters (Kd, Bmax, Ki) were determined from saturation and competition curves using appropriate transformations (Scatchard, Hill) and calculations (Ki = IC50/(1 + [S]/Kd)).[2]

The method describes tissue preparation for in vitro binding assays. Male Sprague-Dawley rats (180-220 g) were killed by decapitation. Brains were rapidly removed and dissected on ice to isolate specific regions (hippocampus, cerebral cortex, thalamus, etc.). These tissues were then processed for membrane preparation as described in the "Enzyme Assay" section. The protocol does not describe a complete in vivo efficacy or pharmacokinetic study involving drug administration to live animals.[2]
The study used male Wistar/ST rats (starting at 9 weeks old, 270-290 g). Food intake was restricted to maintain body weight at 85% of free-feeding levels. Water was available ad libitum.
Impulsive action was assessed using the 3-choice serial reaction time task (3-CSRTT) in operant chambers. Rats were trained daily (5-6 sessions/week) to nose-poke into a lit aperture among three holes after a fixed intertrial interval (ITI, 5s) to receive a food reward. Premature responses (nose pokes during the ITI) were recorded as the primary measure of impulsive action. Training continued until stable performance was achieved with a stimulus duration of 1s.
For drug testing, a within-subjects design was used. Tandospirone citrate (SM-3997) hydrochloride was dissolved in saline and administered intraperitoneally (i.p.) at a volume of 2 ml/kg, 20 minutes before behavioral testing or a food consumption test. Doses tested were 0 (vehicle), 0.1, and 1 mg/kg (calculated as the salt form).
The selective 5-HT_1A receptor antagonist WAY100635 was dissolved in 0.01M phosphate-buffered saline (PBS) and administered subcutaneously (s.c.) at a volume of 1 ml/kg, 30 minutes before testing, at doses of 0.3 mg/kg or 1 mg/kg (calculated as free base). In combination experiments, WAY100635 was injected 30 min pre-test, followed by Tandospirone citrate (SM-3997) (i.p.) 10 min later (20 min pre-test).
Baseline performance was assessed on non-drug days (Mondays and Thursdays), and drug treatments were administered on Tuesdays and Fridays.[3]

[1]. Analysis of tandospirone (SM-3997) interactions with neurotransmitter receptor binding sites. Biol Psychiatry. 1990 Jul 15;28(2):99-109.

[2]. Characterization of the putative anxiolytic SM-3997 recognition sites in rat brain. Life Sci. 1988;42(24):2419-27.

[3]. Tandospirone suppresses impulsive action by possible blockade of the 5-HT1A receptor. J Pharmacol Sci. 2013;122(2):84-92.

Tandospirone citrate is the citrate of tandospirone, consisting of equimolar amounts of citric acid and tandospirone. It is an anti-anxiety drug used to treat anxiety disorders. It has both anxiolytic and antidepressant effects. It contains tandospirone (1+). See also: Tandospirone (note moved to). Tandospirone (SM-3997) is a pyrimidinylpiperazine compound being developed as a novel non-benzodiazepine anti-anxiety drug. [1] Its main pharmacological action is partial agonism of 5-HT₁A receptors. [1] The pharmacological properties of tandospirone are similar to, but not identical to, other anti-anxiety drugs in the same class (buspirone, ixavispirone, piperazine). The main differences include: buspirone has a higher affinity for dopamine D₂ receptors; ixaspirone has a higher affinity for α₁-adrenergic receptors; and piperazine has a lower affinity for 5-HT₁A receptors. These differences may lead to differences in clinical side effects. [1]
This study suggests that both benzodiazepines and pyrimidinylpiperazine anxiolytics (such as tandospirone) ultimately reduce central serotonergic neurotransmission, but their main mechanisms differ: benzodiazepines act through GABA receptors, while tandospirone acts through selective interaction with 5-HT₁A receptors. [1]
Tandoospirone citrate (SM-3997) is a hypothetical non-benzodiazepine anxiolytic. Tandospirone citrate (SM-3997) has a structure that is not related to benzodiazepines and does not interact with the benzodiazepine-GABA receptor complex, and is designed to avoid the sedation and ataxia associated with benzodiazepines. The anxiolytic effect of tandospirone citrate (SM-3997) is thought to be mediated by selective activation of 5-HT-1A receptors, particularly in the hippocampus, a brain region associated with anxiety. This hypothesis is supported by evidence that tandospirone citrate has a high affinity and selective binding to 5-HT-1A receptors, with a binding spectrum similar to that of the 5-HT-1A receptor agonist 8-OH-DPAT, and that its binding is sensitive to GTP (a characteristic of agonists binding to G protein-coupled receptors). [2] Tandospirone citrate (SM-3997) is an anxiolytic drug that is widely used in Japan and China. It is a partial agonist of the 5-HT_1A receptor. This study investigated its effects on impulsive behavior, a risk factor for a variety of mental illnesses. The results showed that acute administration of tandospirone citrate (SM-3997) selectively inhibited impulsive behavior in rats without affecting their attention or motivation for food rewards. The mechanism may involve functional antagonism of 5-HT1A receptors, possibly by blocking presynaptic receptors, thereby enhancing the release of serotonin in specific brain circuits during behavioral inhibition. However, direct evidence of antagonistic effects in vivo is currently lacking. [3] Due to its relatively mild side effects, tandospirone citrate (SM-3997) is considered a potential therapeutic for the treatment of disorders characterized by high impulsivity, such as attention deficit hyperactivity disorder (ADHD), schizophrenia, and borderline personality disorder. [3]

C₂₇H₃₇N₅O₉

575.61

575.259

112457-95-1

Tandospirone; 87760-53-0

60558

White to off-white solid powder

613.9ºC at 760 mmHg

325.1ºC

5.23E-15mmHg at 25°C

0.102

4

13

11

41

799

4

C1C[C@H]2C[C@@H]1[C@H]3[C@@H]2C(=O)N(C3=O)CCCCN4CCN(CC4)C5=NC=CC=N5.C(C(=O)O)C(CC(=O)O)(C(=O)O)O

DMLGUJHNIWGCKM-DPFKZJTMSA-N

InChI=1S/C21H29N5O2.C6H8O7/c27-19-17-15-4-5-16(14-15)18(17)20(28)26(19)9-2-1-8-24-10-12-25(13-11-24)21-22-6-3-7-23-21;7-3(8)1-6(13,5(11)12)2-4(9)10/h3,6-7,15-18H,1-2,4-5,8-14H2;13H,1-2H2,(H,7,8)(H,9,10)(H,11,12)/t15-,16+,17+,18-;

2-hydroxypropane-1,2,3-tricarboxylic acid;(1R,2S,6R,7S)-4-[4-(4-pyrimidin-2-ylpiperazin-1-yl)butyl]-4-azatricyclo[5.2.1.02,6]decane-3,5-dione

SM-3997 citrate; SM 3997 citrate; SM3997 citrate

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)

H2O: ~31.25 mg/mL (~54.3 mM)

Solubility in Formulation 1: 25 mg/mL (43.43 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C).

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