5-HT1A

Buspirone (3 mg/rat, i.p.) inhibits shock-induced ultrasonic vocalization both after systemic injection and after microinjection into the rat's dorsal raphe nucleus, which is home to a large number of somatodendritic 5-HT1A receptors. The inhibition is dose dependent and total. In the rat forced swim test, immobility is reduced by buspirone (20 mg/kg).[4] In a zebrafish model of anxiety, buspirone is a serotonergic (5HT(1A) receptor agonist) anxiolytic medication with some D(2) dopaminergic effect.[5] Buspirone acts at the 5-HT(1A) receptor in l-DOPA-primed rats, which reduces LID and improves l-DOPA-related motor performance in a dose-dependent manner. Buspirone improves the anti-parkinsonian efficacy of l-DOPA while delaying the development of LID, suggesting the potential long-term benefits of 5-HT(1A) agonists for lowering l-DOPA-related side effects in rats that have never taken the drug.[6]

Cell Line: Lymphocytes
Concentration: 0, 4, 20, 40, 200 and 400 µg/mL
Incubation Time: 6 hours
Result: Decreased cell viability in a dose-dependent manner.

Male C57BL/6N mice
1 and 5 mg/kg
Oral gavage and intraperitoneal injection; for 5 days

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Buspirone, a clinically effective non-benzodiazepine anxiolytic drug, caused inhibition of firing of these neurons when given by intravenous (ED50 = 0.011 mg/kg, i.v.), intraperitoneal (ED50 = 0.088 mg/kg, i.p.), and intragastric (effective dose = 1.0-20.0 mg/kg, i.g.) injection. Buspirone also inhibited these cells when it was administered to the outside of recorded neurons by microiontophoresis (effective currents = 2-15 nA). Iontophoretically applied buspirone did not potentiate nor block the effects of iontophoretically applied GABA. Systemic administration of two putative buspirone metabolites (1,2-pyrimidinyl piperazine and 5-hydroxy buspirone) in relatively high doses had a weak effect and no effect, respectively, on dorsal raphe neuronal firing. It is concluded that buspirone potently and directly inhibits the firing of serotonergic dorsal raphe neurons in the rat. Since buspirone inhibits the firing of serotonergic dorsal raphe neurons and binds to 5-HT1A receptors, the present study supports the notion that central serotonergic systems may be involved in the therapeutic effects of anxiolytic drugs.[1]

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In rats, the 5-HT1A receptor full agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the 5-HT1A receptor partial agonists ipsapirone and buspirone dose dependently and completely inhibited shock-induced ultrasonic vocalization after systemic injection and after microinjection into the dorsal raphe nucleus, a brain region rich in somatodendritic 5-HT1A receptors. As compared with injection into the dorsal raphe nucleus, ipsapirone and 8-OH-DPAT were significantly less potent after microinjection into the lateral ventricle or the median raphe nucleus. Depletion of brain 5-HT (5-hydroxytryptamine) by means of 5,7-dihydroxytryptamine or parachlorophenylalanine inhibited ultrasonic vocalization. In lesioned rats, however, ipsapirone (i.p. or dorsal raphe nucleus) and 8-OH-DPAT (dorsal raphe nucleus) retained their ability to inhibit ultrasonic vocalization and, in non-lesioned rats, bilateral injection of ipsapirone, buspirone and 8-OH-DPAT into the dorsal hippocampus and the amygdala - two brain regions rich in postsynaptic 5-HT1A receptors - also inhibited ultrasonic vocalization. In a Geller-Seifter conflict test, i.p. and local injection of 8-OH-DPAT in the dorsal raphe nucleus and the hippocampus selectively enhanced punished responding. It is suggested that both presynaptic and (possibly to a lesser extent) postsynaptic 5-HT1A receptors are involved in the anxiolytic effects of ipsapirone, buspirone, and 8-OH-DPAT.[3]

Absorption, Distribution and Excretion
Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes.
A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion.
In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg.
In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg.

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Metabolism / Metabolites
Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone.
Metabolized hepatically, primarily by oxidation by cytochrome P450 3A4 producing several hydroxylated derivatives and a pharmacologically active metabolite, 1-pyrimidinylpiperazine (1-PP)
Route of Elimination: In a single-dose study using 14C-labeled buspirone, 29% to 63% of the dose was excreted in the urine within 24 hours, primarily as metabolites; fecal excretion accounted for 18% to 38% of the dose.
Half Life: 2-3 hours (although the action of a single dose is much longer than the short halflife indicates).

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Biological Half-Life
In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours.

Hepatotoxicity
Buspirone has been associated with infrequent serum aminotransferase elevations, but has not been linked to instances of clinically apparent liver injury in the published literature. Indeed, buspirone is often used as a control, noncytotoxic agent in assessment of other psychotropic drugs in vitro and in vivo. Buspirone is, nevertheless, metabolized in the liver by the P450 system (CYP 3A4) and has the potential of causing drug-drug interactions.
Likelihood score: E (unlikely cause of clinically apparent liver injury).
Drug Class: Sedatives and Hypnotics, Miscellaneous

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited information indicates that maternal doses of buspirone up to 45 mg daily produce low levels in milk. Because no information is available on the long-term use of buspirone during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Possible drug-induced seizure-like activity and cyanosis occurred in a breastfed 3-week-old whose mother was taking buspirone 15 mg 3 times daily as well as fluoxetine and carbamazepine during pregnancy and breastfeeding. The authors thought that this reaction, if drug induced, was most likely caused by fluoxetine.
One exclusively breastfed 11-week-old infant was breastfed during maternal therapy with buspirone 10 mg daily and venlafaxine 300 mg daily. No adverse reactions were reported by the mother or in the medical records.
◉ Effects on Lactation and Breastmilk
Buspirone increases serum prolactin. Galactorrhea was reported in a woman taking venlafaxine after buspirone was added to her regimen. However, when buspirone was discontinued, galactorrhea persisted. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.
◈ What is buspirone?
Buspirone is a medication that has been used to treat anxiety. The brand name for buspirone is Buspar®.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take your medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy. For more information on anxiety, see our fact sheet here: https://mothertobaby.org/fact-sheets/anxiety-fact/.Some people may have a return of their symptoms (relapse) if they stop this medication. If you plan to stop this medication, your healthcare provider may suggest that you slowly lower the dose instead of stopping all at once. Stopping this medication suddenly can cause some people to have withdrawal symptoms. It is not known what effect, if any, withdrawal could have on a pregnancy.
◈ I take buspirone. Can it make it harder for me to get pregnant?
It is not known if buspirone can make it harder to get pregnant.
◈ Does taking buspirone increase the chance of miscarriage?
Miscarriage is common and can occur in any pregnancy for many different reasons. Studies have not been done to see if buspirone can increase the chance of miscarriage.
◈ Does taking buspirone increase the chance of birth defects?
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. It is not known if buspirone can increase the chance of birth defects above the background risk. Information from a pregnancy registry found no birth defects among 72 infants exposed to buspirone during pregnancy.
◈ Does taking buspirone in pregnancy increase the chance of other pregnancy-related problems?
Studies have not been done to see if buspirone can increase the chance of other pregnancy-related problems, such as preterm delivery (birth before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth).
◈ I need to take buspirone throughout my entire pregnancy. Will it cause withdrawal symptoms in my baby after birth?
The use of some medications during pregnancy can cause temporary symptoms in newborns soon after birth. These symptoms are sometimes referred to as withdrawal. There is a report of one infant with decreased growth, tremors, low muscle tone, low blood sugar, and trouble feeding. The infant was exposed to buspirone, other medications, and cigarette smoke during pregnancy. It is not known if the symptoms in the baby were due to buspirone, other exposures, or a combination of factors. It is important that your healthcare providers know you are taking buspirone so your baby can be monitored if needed.
◈ Does taking buspirone in pregnancy affect future behavior or learning for the child?
Studies have not been done to see if buspirone can increase the chance of behavior or learning issues for the child.
◈ Breastfeeding while taking buspirone:
Information on the use of buspirone in breastfeeding is limited. One report included a person who took buspirone (15mg/ 3 times a day) while breastfeeding. The levels of the medication were checked once and were too low to be found in the breastmilk. There are reports that looked at effects of buspirone in breastfed infants. One report found no short-term side effects in an 11-week-old baby whose mother was taking 2 medications including 10 mg/day of buspirone. Another report described seizure-like activity in a 3-week-old infant. However, the authors suggested that if one of the 3 prescription medications that the mother was taking contributed to the effects seen in the baby, it was unlikely to be buspirone. If you suspect the baby has any symptoms, contact the child’s healthcare provider. Be sure to talk to your healthcare provider about all your breastfeeding questions.
◈ If a male takes buspirone, could it affect fertility or increase the chance of birth defects?
It is not known if buspirone could affect male fertility (ability to get partner pregnant) or increase the chance of birth defects above the background risk. Studies by the manufacturer reported decreased libido (less desire to have sex), delayed ejaculation, and impotence (inability to get and maintain an erection). These issues can affect male fertility. In general, exposures that fathers or sperm donors have are unlikely to increase risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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Protein Binding
Based on the findings of an _in vitro_ protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein.

[1]. Eur J Pharmacol . 1986 Sep 23;129(1-2):123-30.

[2]. Am J Med . 1986 Mar 31;80(3B):41-51.

[3]. Eur J Pharmacol . 1993 Nov 16;249(3):341-51.

[4]. Pharmacol Biochem Behav . 2009 Nov;94(1):75-80.

[5]. Pharmacol Biochem Behav . 2007 Aug-Sep;87(3):306-14.

Buspirone is an azaspiro compound that is 8-azaspiro[4.5]decane-7,9-dione substituted at the nitrogen atom by a 4-(piperazin-1-yl)butyl group which in turn is substituted by a pyrimidin-2-yl group at the N(4) position. It has a role as an anxiolytic drug, a sedative, a serotonergic agonist and an EC 3.4.21.26 (prolyl oligopeptidase) inhibitor. It is an azaspiro compound, a member of pyrimidines, a N-arylpiperazine, a N-alkylpiperazine, a member of piperidones and an organic heteropolycyclic compound. It is a conjugate base of a buspirone(1+).
Buspirone is a novel anxiolytic agent with a unique structure and a pharmacological profile. Belonging to the azaspirodecanedione drug class, buspirone is a serotonin 5-HT1A receptor agonist that is not chemically or pharmacologically related to benzodiazepines, barbiturates, and other sedative/anxiolytic drugs. Unlike many drugs used to treat anxiety, buspirone does not exhibit anticonvulsant, sedative, hypnotic, and muscle-relaxant properties. Due to these characteristics, buspirone been termed 'anxioselective'. First synthesized in 1968 then patented in 1975, it is commonly marketed under the brand name Buspar®. Buspirone was first approved in 1986 by the FDA and has been used to treat anxiety disorders, such as generalized anxiety disorder (GAD), and relieve symptoms of anxiety. It has also been used as a second-line therapy for unipolar depression when the use of selective serotonin reuptake inhibitors (SSRIs) is deemed clinically inadequate or inappropriate. The potential use of buspirone in combination with [melatonin] in depression and cognitive impairment via promoting neurogenesis has also been investigated.
Buspirone is a psychoactive drug used for management of general anxiety disorders and alleviation of the symptoms of anxiety. Despite wide scale use, it is an infrequent cause of serum enzyme elevations and has not been linked to instances of clinically apparent liver injury with jaundice.
Buspirone is an anxiolytic agent chemically and pharmacologically unrelated to benzodiazepines, barbiturates, or other sedative/hypnotic drugs. Although its exact mechanism of action is unknown, buspirone may exert its anti-anxiety effects via serotonin (5-HT1A) and dopamine receptors (D2) and may indirectly affect other neurotransmitter systems. Unlike typical benzodiazepine anxiolytics, this agent does not exert anticonvulsant or muscle relaxant effects and lacks prominent sedative effects.
Buspirone is only found in individuals that have used or taken this drug. It is an anxiolytic agent and a serotonin receptor agonist belonging to the azaspirodecanedione class of compounds. Its structure is unrelated to those of the benzodiazepines, but it has an efficacy comparable to diazepam. Buspirone binds to 5-HT type 1A serotonin receptors on presynaptic neurons in the dorsal raphe and on postsynaptic neurons in the hippocampus, thus inhibiting the firing rate of 5-HT-containing neurons in the dorsal raphe. Buspirone also binds at dopamine type 2 (DA2) receptors, blocking presynaptic dopamine receptors. Buspirone increases firing in the locus ceruleus, an area of brain where norepinephrine cell bodies are found in high concentration. The net result of buspirone actions is that serotonergic activity is suppressed while noradrenergic and dopaminergic cell firing is enhanced.
An anxiolytic agent and serotonin receptor agonist belonging to the azaspirodecanedione class of compounds. Its structure is unrelated to those of the BENZODIAZAPINES, but it has an efficacy comparable to DIAZEPAM.
See also: Buspirone Hydrochloride (has salt form).

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Drug Indication
Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety.

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Mechanism of Action
The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT_1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT_1A receptors, or 5-HT_1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT_1A receptors expressed on hippocampus and cortex. 5-HT_1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT_1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT_1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT_1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist.

C21H32CLN5O2

421.96

421.224

C, 59.77; H, 7.64; Cl, 8.40; N, 16.60; O, 7.58

33386-08-2

Buspirone; 36505-84-7; Buspirone-d8 hydrochloride; 1216761-39-5

2477

White crystalline powder

1.24g/cm3

613.9ºC at 760mmHg

201.5-202.50C

325.1ºC

2.831

0

6

6

28

529

0

O=C(N(CCCCN1CCN(C2=NC=CC=N2)CC1)C(C3)=O)CC43CCCC4.[H]Cl

RICLFGYGYQXUFH-UHFFFAOYSA-N

InChI=1S/C21H31N5O2.ClH/c27-18-16-21(6-1-2-7-21)17-19(28)26(18)11-4-3-10-24-12-14-25(15-13-24)20-22-8-5-9-23-20;/h5,8-9H,1-4,6-7,10-17H2;1H

8-[4-(4-pyrimidin-2-ylpiperazin-1-yl)butyl]-8-azaspiro[4.5]decane-7,9-dione;hydrochloride

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.92 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 25.0 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.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.92 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 25.0 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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.92 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 15% Captisol, pH 9: 10 mg/mL

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Solubility in Formulation 5: 100 mg/mL (236.99 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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