Buspirone

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Buspirone 200.svg

Buspirone

 

Buspirone

  • Molecular FormulaC21H31N5O2
  • Average mass385.503 Da
  • буспирон
    بوسبيرون
    丁螺酮
251-489-4 [EINECS]
253-072-2 [EINECS]
36505-84-7 [RN]
8-[4-(4-Pyrimidin-2-yl-piperazin-1-yl)-butyl]-8-aza-spiro[4.5]decane-7,9-dione
8-[4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione
  • 8-[4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione
  • Buspin
  • Buspirone
  • Spitomin
Buspirone
CAS Registry Number: 36505-84-7
CAS Name: 8-[4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione
Molecular Formula: C21H31N5O2
Molecular Weight: 385.50
Percent Composition: C 65.43%, H 8.11%, N 18.17%, O 8.30%
Literature References: Non-benzodiazepine anxiolytic; 5-hydroxytryptamine (5-HT1) receptor agonist. Prepn: Y. H. Wu et al., J. Med. Chem. 15, 477 (1972); Y. H. Wu, J. W. Rayburn, DE 2057845 (1971 to Bristol-Myers); eidem, US 3717634 (1973 to Mead-Johnson). Pharmacology: L. E. Allen et al., Arzneim.-Forsch. 24, 917 (1974). Comparison with diazepam in treatment of anxiety: H. L. Goldberg, R. J. Finnerty, Am. J. Psychiatry 136, 1184 (1979); A. F. Jacobson et al., Pharmacotherapy 5, 290 (1985). Nonsynergistic effect with alcohol: T. Seppala et al., Clin. Pharmacol. Ther. 32, 201 (1982). Disposition and metabolism: S. Caccia et al., Xenobiotica 13, 147 (1983). Series of articles on chemistry, pharmacology, addictive potential, and clinical trials: J. Clin. Psychiatry 43, pp 1-116 (1982); on pharmacology, safety and clinical comparison with clorazepate: Am. J. Med. 80, Suppl. 3B, 1-51 (1986). Review of pharmacology and therapeutic efficacy: K. L. Goa, A. Ward, Drugs 32, 114-129 (1986). Review: M. W. Jann, Pharmacotherapy 8, 100-116 (1988); D. P. Taylor, FASEB J. 2, 2445-2452 (1988).
Derivative Type: Hydrochloride
CAS Registry Number: 33386-08-2
Trademarks: Ansial (Vita); Ansiced (Abello); Axoren (Glaxo Wellcome); Bespar (BMS); Buspar (BMS); Buspimen (Menarini); Buspinol (Zdravlje); Buspisal (Lesvi); Narol (Almirall)
Molecular Formula: C21H31N5O2.HCl
Molecular Weight: 421.96
Percent Composition: C 59.77%, H 7.64%, N 16.60%, O 7.58%, Cl 8.40%
Properties: Crystals from abs ethanol, mp 201.5-202.5°. LD50 i.p. in rats: 136 mg/kg (Allen).
Melting point: mp 201.5-202.5°
Toxicity data: LD50 i.p. in rats: 136 mg/kg (Allen)
Therap-Cat: Anxiolytic.
Keywords: Anxiolytic; Arylpiperazines; Serotonin Receptor Agonist.

Buspirone, sold under the brand name Buspar, among others, is a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder.[9][10] Benefits support its short term use.[11] It has not been found to be effective in treating psychosis.[9] It is taken by mouth, and it may take up to four weeks to have an effect.[9][10]

Common side effects of buspirone include nausea, headaches, dizziness, and difficulty concentrating.[9][11] Serious side effects may include hallucinationsserotonin syndrome, and seizures.[11] Its use in pregnancy appears to be safe but has not been well studied, while use during breastfeeding is not recommended.[11][12] It is a serotonin 5-HT1A receptor agonist.[2]

Buspirone was first made in 1968 and approved for medical use in the United States in 1986.[9][10] It is available as a generic medication.[11] In 2018, it was the 92nd most-commonly prescribed medication in the United States, with more than 8 million prescriptions.[13][14]

Medical uses

Anxiety

Buspirone is used for the short-term treatment of anxiety disorders or symptoms of anxiety.[15][16][17][18][19] It is generally less preferred than selective serotonin reuptake inhibitors (SSRIs).[10]

Buspirone has no immediate anxiolytic effects, and hence has a delayed onset of action; its full clinical effectiveness may require 2–4 weeks to manifest itself.[20] The drug has been shown to be similarly effective in the treatment of generalized anxiety disorder (GAD) to benzodiazepines including diazepamalprazolamlorazepam, and clorazepate.[2] Buspirone is not known to be effective in the treatment of other anxiety disorders besides GAD,[21] although there is some limited evidence that it may be useful in the treatment of social phobia as an adjunct to selective serotonin reuptake inhibitors (SSRIs).[2][22]

Other uses

Sexual dysfunction

There is some evidence that buspirone on its own may be useful in the treatment of hypoactive sexual desire disorder (HSDD) in women.[23]

Miscellaneous

Buspirone is not effective as a treatment for benzodiazepine withdrawalbarbiturate withdrawal, or alcohol withdrawal/delirium tremens.[24]

SSRI and SNRI antidepressants such as paroxetine and venlafaxine may cause jaw pain/jaw spasm reversible syndrome (although it is not common), and buspirone appears to be successful in treating bruxism on SSRI/SNRI-induced jaw clenching.[25][26]

Contraindications

Buspirone has these contraindications:[27][28]

Side effects

Known side effects associated with buspirone include dizzinessheadachesnauseanervousness, and paresthesia.[2] Buspirone is relatively well tolerated, and is not associated with sedationcognitive and psychomotor impairmentmuscle relaxationphysical dependence, or anticonvulsant effects.[2] In addition, buspirone does not produce euphoria[20] and is not a drug of abuse.[16]

It is unclear if there is a risk of tardive dyskinesia or other movement disorders with buspirone.[9]

Overdose

Buspirone appears to be relatively benign in cases of single-drug overdose, although no definitive data on this subject appear to be available.[29] In one clinical trial, buspirone was administered to healthy male volunteers at a dosage of 375 mg/day, and produced side effects including nauseavomitingdizzinessdrowsinessmiosis, and gastric distress.[15][16][18] In early clinical trials, buspirone was given at dosages even as high as 2,400 mg/day, with akathisiatremor, and muscle rigidity observed.[30] Deliberate overdoses with 250 mg and up to 300 mg buspirone have resulted in drowsiness in about 50% of individuals.[30] One death has been reported in association with 450 mg buspirone together with alprazolamdiltiazemalcoholcocaine.[30]

Interactions

Buspirone has been shown in vitro to be metabolized by the enzyme CYP3A4.[8] This finding is consistent with the in vivo interactions observed between buspirone and these inhibitors or inducers of cytochrome P450 3A4 (CYP3A4), among others:[27]

Elevated blood pressure has been reported when buspirone has been administered to patients taking monoamine oxidase inhibitors (MAOIs).[27]

Pharmacology

Pharmacodynamics

Buspirone[33]
Site Ki (nM) Species Ref
5-HT1A 3.98–214
21 (median)
Human [33][34]
5-HT1B >100,000 Rat [35]
5-HT1D 22,000–42,700 Human [36][37]
5-HT2A 138
759–1,300
Human
Rat
[38]
[35][38]
5-HT2B 214 Human [38]
5-HT2C 490
1,100–6,026
Human
Rat/pig
[38]
[35][38]
5-HT3 >10,000 Rat [39][40]
5-HT4 >10,000 Rat [40]
5-HT6 398 Mouse [41]
5-HT7 375–381 Rat [42][43]
α1 1,000 Rat [35]
α2 6,000 Rat [44]
  α2A 7.3 (1-PP) Human [35]
β 8,800 Rat [35]
D1 33,000 Rat [35]
D2 484
240
Human
Rat
[45]
[35]
D3 98 Human [45]
D4 29 Human [45]
mACh 38,000 Rat [35]
GABAA
(BDZ)
>100,000 Rat [35]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Buspirone acts as an agonist of the serotonin 5-HT1A receptor with high affinity.[2][35] It is a partial agonist of both presynaptic 5-HT1A receptors, which are inhibitory autoreceptors, and postsynaptic 5-HT1A receptors.[2] It is thought that the main effects of buspirone are mediated via its interaction with the presynaptic 5-HT1A receptor, thus reducing the firing of serotonin-producing neurons.[2] Buspirone also has lower affinities for the serotonin 5-HT2A5-HT2B5-HT2C5-HT6, and 5-HT7 receptors.[33]

In addition to binding to serotonin receptors, buspirone is an antagonist of the dopamine D2 receptor with weak affinity.[2][35] It preferentially blocks inhibitory presynaptic D2 autoreceptors, and antagonizes postsynaptic D2 receptors only at higher doses.[2] In accordance, buspirone has been found to increase dopaminergic neurotransmission in the nigrostriatal pathway at low doses, whereas at higher doses, postsynaptic D2 receptors are blocked and antidopaminergic effects such as hypoactivity and reduced stereotypy, though notably not catalepsy, are observed in animals.[2] Buspirone has also been found to bind with much higher affinity to the dopamine D3 and D4 receptors, where it is similarly an antagonist.[45]

A major metabolite of buspirone, 1-(2-pyrimidinyl)piperazine (1-PP), occurs at higher circulating levels than buspirone itself and is known to act as a potent α2-adrenergic receptor antagonist.[44][46][47] This metabolite may be responsible for the increased noradrenergic and dopaminergic activity observed with buspirone in animals.[46][48] In addition, 1-PP may play an important role in the antidepressant effects of buspirone.[48] Buspirone also has very weak and probably clinically unimportant affinity for the α1-adrenergic receptor.[35][49] However, buspirone has been reported to have shown “significant and selective intrinsic efficacy” at the α1-adrenergic receptor expressed in a “tissue- and species-dependent manner”.[49]

Unlike benzodiazepines, buspirone does not interact with the GABAA receptor complex.[2][50]

Pharmacokinetics

Buspirone has a low oral bioavailability of 3.9% relative to intravenous injection due to extensive first-pass metabolism.[2] The time to peak plasma levels following ingestion is 0.9 to 1.5 hours.[2] It is reported to have an elimination half-life of 2.8 hours,[2] although a review of 14 studies found that the mean terminal half-life ranged between 2 and 11 hours, and one study even reported a terminal half-life of 33 hours.[4] Buspirone is metabolized primarily by CYP3A4, and prominent drug interactions with inhibitors and inducers of this enzyme have been observed.[7][8] Major metabolites of buspirone include 5-hydroxybuspirone, 6-hydroxybuspirone, 8-hydroxybuspirone, and 1-PP.[4][5][6] 6-Hydroxybuspirone has been identified as the predominant hepatic metabolite of buspirone, with plasma levels that are 40-fold greater than those of buspirone after oral administration of buspirone to humans.[5] The metabolite is a high-affinity partial agonist of the 5-HT1A receptor (Ki = 25 nM) similarly to buspirone, and has demonstrated occupancy of the 5-HT1A receptor in vivo.[5] As such, it is likely to play an important role in the therapeutic effects of buspirone.[5] 1-PP has also been found to circulate at higher levels than those of buspirone itself and may similarly play a significant role in the clinical effects of buspirone.[46][48]

Phase I Metabolism of buspirone in humans[51][52][8]

History

Buspirone was first synthesized, by a team at Mead Johnson, in 1968,[21] but was not patented until 1975.[54][55] It was initially developed as an antipsychotic drug acting on the D2 receptor, but was found to be ineffective in the treatment of psychosis; it was then used as an anxiolytic instead.[2] In 1986, Bristol-Myers Squibb gained FDA approval for buspirone in the treatment of GAD.[21][56] The patent placed on buspirone expired in 2001 and it is now available as a generic drug.

Society and culture

Buspar (buspirone) 10-mg tablets

Generic names

Buspirone is the INNBANDCF, and DCIT of buspirone, while buspirone hydrochloride is its USANBANM, and JAN.[1][57][58][59]

Brand name

Buspirone was primarily sold under the brand name Buspar.[57][59] Buspar is currently listed as discontinued by the US Federal Drug Administration.[60] In 2010, in response to a citizen petition, the US FDA determined that Buspar was not withdrawn for sale because of reasons of safety or effectiveness.[61]

2019 shortage

Due to interrupted production at a Mylan Pharmaceuticals plant in Morgantown, West Virginia, the United States experienced a shortage of buspirone in 2019.[62]

Research

Some tentative research supports other uses such as the treatment of depression and behavioral problems following brain damage.[2]

Chemistry

Buspirone is a member of the azapirone chemical class, and consists of azaspirodecanedione and pyrimidinylpiperazine components linked together by a butyl chain.

Analogues

Structural analogues of buspirone include other azapirones like gepironeipsapironeperospirone, and tandospirone.[53]

Synthesis

Alkylation of 1-(2-pyrimidyl)piperazine (1) with 3-chloro-1-cyanopropane (2, 4-chlorobutyronitrile) gives 3, which is reduced either by hydrogenation over Raney nickel catalyst, or with LAH. The resulting 1° amine (4) from the previous step is then reacted with 3,3-tetramethyleneglutaric anhydride (5, 8-Oxaspiro[4.5]decane-7,9-dione) in order to yield buspirone (6).

PAPERS

  1. Koziol, Anna E.; Acta Crystallographica, Section E: Structure Reports Online 2006, V62(12), Po5616-o5618 
  2. Mou, Jie; Organic Preparations and Procedures International 2008, V40(4), P391-394 
  3. Kairisalo, Pekka Juhani; FI 72975 B 1987 
  4. Journal of medicinal chemistry (1983), 26(2), 194-203
  5. Journal of medicinal chemistry (1986), 29(8), 1476-82.
  6. Medicinal research reviews (1990), 10(3), 283-326.
  7. Heterocycles (1993), 36(7), 1463-9
  8. Journal of medicinal chemistry (1996), 39(5), 1125-9.
  9. Journal of medicinal chemistry (1996), 39(16), 3195-202.
  10. Nature Catalysis, 3(10), 843-850; 2020

PAPER

https://pubs.rsc.org/en/content/articlelanding/2019/GC/C8GC03328E#!divAbstract

  1. Green Chemistry, 21(1), 59-63; 2019

Abstract

A continuous flow method for the direct conversion of alcohols to amines via a hydrogen borrowing approach is reported. The method utilises a low loading (0.5%) of a commercial catalyst system ([Ru(p-cymene)Cl2]2 and DPEPhos), reagent grade solvent and is selective for primary alcohols. Successful methylation of amines using methanol and the direct dimethylamination of alcohols using commercial dimethylamine solution are reported. The synthesis of two pharmaceutical agents Piribedil (5) and Buspirone (25) were accomplished in good yields employing these new methods.

Graphical abstract: Fast continuous alcohol amination employing a hydrogen borrowing protocol
http://www.rsc.org/suppdata/c8/gc/c8gc03328e/c8gc03328e2.pdf
8-(4-hydroxybutyl)-8-azaspiro[4.5]decane-7,9-dione (23): A solution of 3,3-tetramethyleneglutaric anhydride (0.25 mol/L in THF) was combined in a tee piece with a solution of 4-amino-1-butanol (0.25 mol/L in THF) and reacted in a 20 mL reactor coil (stainless steel, 20 min residence time) heated at 250 °C. The output was concentrated in vacuo and the residue purified by column chromatography on silica gel to afford the product in 84% yield (Rf = 0.31, 63% DCM/AcOEt). 1H NMR (400 MHz, CDCl3) δ = 3.78 (t, J = 7.2 Hz, 2H), 3.65 (t, J = 6.0 Hz, 2H), 2.58 (s, 4H), 1.77 – 1.64 (m, 4H), 1.64 – 1.53 (m, 4H), 1.53 – 1.43 (m, 4H). 13C NMR (100 MHz, CDCl3) δ = 172.33, 62.28, 44.87, 39.47, 39.14, 37.54, 29.81, 24.35, 24.17. HRMS for [C13H22NO3] + calculated 240.1594 found 240.1605.
8-(4-(4-(pyrimidin-2-yl)piperazin-1-yl)butyl)-8-azaspiro[4.5]decane-7,9-dione (Buspirone, 25): The flow system was flushed with THF, the back-pressure regulator was set to 50 bar, and the coil reactor heated to 250 °C. Then a solution (10 mL overall volume) containing 1-(2-pyrimidyl)piperazine (2 mmol), 8-(4-hydroxybutyl)- 8-azaspiro[4.5]decane-7,9-dione (23) (2 mmol), dichloro(p-cymene)ruthenium(II) dimer (0.08 mmol) and bis[(2- diphenylphosphino)phenyl] ether (DPEPhos, 0.17 mmol) was pumped at 0.8 ml/min through a heated coil (8 mL, Phoenix reactor). The output solution obtained in steady state (monitored using the FlowUV) was concentrated in vacuo and purified by column chromatography on silica gel to afford the desired product in 76% yield (Rf = 0.29, 5% MeOH/DCM). 1H NMR (400 MHz, CDCl3) δ = 8.31 (d, J = 4.7 Hz, 2H), 6.48 (t, J = 4.7 Hz, 1H), 3.84 (t, J = 5.1 Hz, 4H), 3.79 (t, J = 6.8 Hz, 2H), 2.60 (s, 4H), 2.50 (t, J = 5.1 Hz, 4H), 2.40 (t, J = 6.8 Hz, 2H), 1.79 – 1.65 (m, 4H), 1.65 – 1.42 (m, 8H). 13C NMR (100 MHz, CDCl3) δ = 172.19, 161.63, 157.68, 109.77, 58.31, 53.06, 44.92, 43.60, 39.48, 39.35, 37.56, 26.04, 24.19, 24.19. HRMS for [C21H32N5O2] + calculated 386.2551 found 386.2570.

 

PAPER

Organic Preparations and Procedures International, 40(4), 391-394; 2008

https://www.tandfonline.com/doi/abs/10.1080/00304940809458099

 

PATENTS

US 3907801

ES 526304

EP 395192

EP 565274

EP 634411

EP 680961

US 5521313

Indian Pat. Appl., 2011MU01860,

PATENTS

WO 2014152737

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014152737

Syn

J Med Chem 1972,15(5),477-479

DE 2057845; FR 2073406; GB 1332194; US 3717634

The condensation of 1-(2-pyrimidinyl)piperazine (I) with 3-chloro-1-cyanopropane (II) by means of Na2CO3 in n-butanol gives 4-(2-pyrimidinyl)-1-(3-cyanopropyl)piperazine (III). This product is reduced with LiAlH4 or with H2 and Raney-Ni yielding 4-(2-pyrimidinyl)-1-(4-aminobutyl)piperazine (IV), which is finally condensed with 8-oxaspiro[4.5]decane-7,9-dione-(3,3-tetramethylene-glutaric anhydride) (V) in pyridine.

CLIP

Anxiolytics (Tranquilizers)

R.S. Vardanyan, V.J. Hruby, in Synthesis of Essential Drugs, 2006

Buspirone

Buspirone, 8-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-8-azaspiro [4,5] decan-7,9-dione (5.2.6), is synthesized by the reaction of 1-(2-pyrimidyl)-4-(4-aminobutyl)piperazine (5.2.4) with 8-oxaspiro[4,5]decan-7,9-dione (5.2.5). In turn, 1-(2-pyrimidyl)-4-(4-aminobutyl)piperazine (5.2.4) is synthesized by the reaction of 1-(2-pyrimidyl)piperazine with 4-chlorobutyronitrile, giving 4-(2-pyrimidyl)-1-(3-cyanopropyl)piperazine (5.2.3), which is hydrogenated with Raney nickel into buspirone (5.2.4) [51–55].

Buspirone is an extremely specific drug that could possibly represent a new chemical class of anxiolytics—azaspirones. As an anxiolytic, its activity is equal to that of benzodiazepines; however, it is devoid of anticonvulsant and muscle relaxant properties, which are characteristic of benzodiazepines. It does not cause dependence or addiction. The mechanism of its action is not conclusively known. It does not act on the GABA receptors, which occurs in benzodiazepine use; however, it has a high affinity for seratonin (5-HT) receptors and a moderate affinity for dopamine (D2) receptors. Buspirone is effective as an anxiolytic. A few side effects of buspirone include dizziness, drowsiness, headaches, nervousness, fatigue, and weakness. This drug is intended for treatment of conditions of anxiety in which stress, muscle pain, rapid heart rate, dizziness, fear, etc. are observed; in other words, conditions of anxiety not associated with somewhat common, usual, and everyday stress. Synonyms for buspirone are anizal, axoren, buspar, buspimen, buspinol, narol, travin, and others.

CLIP

Applications of Biocatalysis for Pharmaceuticals and Chemicals

Ramesh N. Patel, in Organic Synthesis Using Biocatalysis, 2016

5.2 Enzymatic Preparation of 6-Hydroxybuspirone

Buspirone (Buspar®59, Figure 11.17) is a drug used for the treatment of anxiety and depression, thought to produce its effects by binding to the serotonin 5HT1A receptor [114–116]. Mainly as a result of hydroxylation reactions, it is extensively converted to various metabolites and blood concentrations return to low levels a few hours after dosing [117]. A major metabolite, 6-hydroxybuspirone, produced by the action of liver cytochrome P450 CYP3A4, was present at much higher concentrations in human blood than buspirone itself. For development of 6-hydroxybuspirone as a potential antianxiety drug, preparation and testing of the two enantiomers as well as the racemate was of interest. An enantioselective microbial reduction process was developed for the reduction of 6-oxobuspirone 60 to (R)-6-hydroxybuspirone 61a or (S)-6-hydroxybuspitone 61b. About 150 microbial cultures were screened for the enantioselective reduction of 60Rhizopus stolonifer SC 13898, Neurospora crassa SC 13816, Mucor racemosus SC 16198, and Pseudomonas putida SC 13817 gave >50% reaction yields and >95% ee of (S)-6-hydroxybuspirone 61a. The yeast strains Hansenula polymorpha SC 13845 and Candida maltosa SC 16112 gave (R)-6-hydroxybuspirone in >60% reaction yield and >97% ee [118]. The NADPH-dependent (R)-reductase (RHBR) from H. polymorpha SC 13845 was purified to homogeneity, its N-terminal and internal amino acid sequences were determined and the corresponding gene was cloned and expressed in E. coli. To regenerate the NADPH required for reduction, glucose-6-phosphate dehydrogenase gene from Saccharomyces cerevisiae was cloned and coexpressed in the same E. coli strain. Recombinant cultures coexpressing (R)-reductase (RHBR) and glucose 6-phosphate dehydrogenase catalyzed the reduction of 6-ketobuspirone to (R)-6-hydroxybuspirone 61a in 99% yield and 99.9% ee at 50 g/L substrate input [119].

Figure 11.17. Enzymatic preparation of 6-hydroxybuspirone.

The NADH-dependent (S)-reductase (SHBR) from P. putida SC 16269 was also purified to homogeneity, its N-terminal and internal amino acid sequences were determined and the corresponding gene was cloned and expressed in E. coli. To regenerate the NADH required for reduction, the NAD+ dependent formate dehydrogenase gene from Pichia pastoris was also cloned and co-expressed in the same E. coli strain. Recombinant E. coli coexpressing (S)-reductase and formate dehydrogenase was used to catalyze the reduction of 6-ketobuspirone to (S)-6-hydroxybuspirone 61b, in >98% yield and >99.8% ee at 50 g/L substrate input [119].

PATENT

https://patents.google.com/patent/US6686361

The present invention relates to methods of treating anxiety and depression using R-6-hydroxy-buspirone and pharmaceutical compositions containing R-6-hydroxy-buspirone.

Buspirone, chemically: 8-[4-[4-(2-pyrimidinyl)1-piperazinyl]butyl-8-azaspiro(4,5)-decane-7,9-dione, is approved for the treatment of anxiety disorders and depression by the United States Food and Drug Administration. It is available under the trade name BUSPAR® from Bristol-Myers Squibb Company.

Studies have shown that buspirone is extensively metabolized in the body. (See, for example, Mayol, et al., Clin. Pharmacol. Ther., 37, p. 210, 1985). One of the metabolites is 6-hydroxy-8-[4-[4-(2-pyrimidinyl)1-piperazinyl]butyl-8-azaspiro(4,5)-decane-7,9-dione having Formula I. This metabolite is also known as BMS 28674, BMS 442608, or

Figure US06686361-20040203-C00001

as 6-hydroxy-buspirone. This compound is believed to be the active metabolite of buspirone and its use in treating anxiety disorders and depression is disclosed in U.S. Pat. No. 6,150,365. The specific stereochemistry of 6-hydroxy-buspirone has not been described previously. Neither racemic 6-hydroxy-buspirone nor its enantiomers are commercially available at the present time.

Preclinical studies demonstrate that 6-hydroxy-buspirone, like buspirone, demonstrates a strong affinity for the human 5-HT1A receptor. In functional testing, 6-hydroxy-buspirone produced a dose-dependent anxiolytic response in the rat pup ultrasonic vocalization test, a sensitive method for assessment of anxiolytic and anxiogenic effects (Winslow and Insel, 1991, Psychopharmacology, 105:513-520).

Clinical studies in volunteers orally dosed with buspirone demonstrate that 6-hydroxy-buspirone blood plasma levels were not only 30 to 40 times higher but were sustained compared to buspirone blood plasma levels. The time course of 6-hydroxy-buspirone blood plasma levels, unlike buspirone blood plasma levels, correlate more closely with the sustained anxiolytic effect seen following once or twice a day oral dosing with buspirone.

Although buspirone is an effective treatment for anxiety disorders and depression symptomatology in a significant number of patients treated, about a third of patients get little to no relief from their anxiety and responders often require a week or more of buspirone treatment before experiencing relief from their anxiety symptomatology. Further, certain adverse effects are reported across the patient population. The most commonly observed adverse effects associated with the use of buspirone include dizziness, nausea, headache, nervousness, lightheadedness, and excitement. Also, since buspirone can bind to central dopamine receptors, concern has been raised about its potential to cause unwanted changes in dopamine-mediated neurological functions and a syndrome of restlessness, appearing shortly after initiation of oral buspirone treatment, has been reported in small numbers of patients. While buspirone lacks the prominent sedative effects seen in more typical anxiolytics such as the benzodiazepines, patients are nonetheless advised against operating potentially dangerous machinery until they experience how they are affected by buspirone.

It can be seen that it is desirable to find a medicament with buspirone’s advantages but which demonstrates more robust anxiolytic potency with a lack of the above described adverse effects.

Formation of 6-hydroxy-buspirone occurs in the liver by action of enzymes of the P450 system, specifically CYP3A4. Many substances such as grapefruit juice and certain other drugs; e.g. erythromycin, ketoconazole, cimetidine, etc., are inhibitors of the CYP3A4 isozyme and may interfere with the formation of this active metabolite from buspirone. For this reason it would be desirable to find a compound with the advantages of buspirone but without the drug—drug interactions when coadministered with agents affecting the activity level of the CYP3A4 isozyme.

EXAMPLE 3One-Step Synthesis of 6-Hydroxy-buspirone (I)

Buspirone (19.3 g, 50 mmole) was dissolved in dry THF (400 mL) and the resulting solution was cooled to −78° C. A solution of KN(SiMe3)in toluene (100 mL, 1 M) was added slowly. After the reaction mixture was stirred at −78° C. for 1 h, a solution of 2-(phenylsulfonyl)-3-phenyloxaziridine (Davis reagent, prepared according to literature method: F. A. Davis, et al., Org. Synth., 1988, 66, 203) (17.0 g, 65 mmole) in dry THF (150 mL, precooled to −78° C.) was added quickly via a cannular. After stirred for 30 mins at −78° C., the reaction was quenched with 1 N HCl solution (500 mL). It was extracted with EtOAc (3×500 mL). The aqueous layer was separated, neutralized with saturated sodium bicarbonate solution, and extracted with EtOAc (3×500 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a white solid residue which was subjected to column chromatography using CH2Cl2/MeOH/NH4OH (200:10:1) as the eluent to give pure 6-hydroxy-buspirone (I, 7.2 g) and a mixture of buspirone and 6-hydroxy-buspirone (I). The mixture was purified by above column chromatography to afford another 3.3 g of pure 6-hydroxy-buspirone (I).

1H NMR (CDCl3) δ8.30 (d, J=4.7 Hz, 2H), 6.48 (t, J=4.7 Hz, 1H), 4.20 (s, 1H), 3.83-3.72 (m, 5H), 3.55 (s, 1H), 2.80 (d, J=17.5 Hz, 1H), 2.55-2.40 (m, 7H), 2.09-2.03 (m, 1H), 1.76-1.54 (m, 10 H), 1.41-1.36 (m, 1H), 1.23-1.20 (m, 1H).

References

  1. Jump up to:a b Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 192–. ISBN 978-1-4757-2085-3.
  2. Jump up to:a b c d e f g h i j k l m n o p q r Loane C, Politis M (June 2012). “Buspirone: what is it all about?”. Brain Research1461: 111–8. doi:10.1016/j.brainres.2012.04.032PMID 22608068S2CID 11734819.
  3. Jump up to:a b c “buspirone (Rx) – BuSpar, Buspirex, more.” Medscape Reference. WebMD. Retrieved 14 November 2013.
  4. Jump up to:a b c Gammans RE, Mayol RF, LaBudde JA (March 1986). “Metabolism and disposition of buspirone”. The American Journal of Medicine80 (3B): 41–51. doi:10.1016/0002-9343(86)90331-1PMID 3515929.
  5. Jump up to:a b c d e Schatzberg AF, Nemeroff CB (2009). The American Psychiatric Publishing Textbook of Psychopharmacology. American Psychiatric Pub. pp. 490–. ISBN 978-1-58562-309-9.
  6. Jump up to:a b Wong H, Dockens RC, Pajor L, Yeola S, Grace JE, Stark AD, et al. (August 2007). “6-Hydroxybuspirone is a major active metabolite of buspirone: assessment of pharmacokinetics and 5-hydroxytryptamine1A receptor occupancy in rats”. Drug Metabolism and Disposition35 (8): 1387–92. doi:10.1124/dmd.107.015768PMID 17494642S2CID 25558546.
  7. Jump up to:a b c Mahmood I, Sahajwalla C (April 1999). “Clinical pharmacokinetics and pharmacodynamics of buspirone, an anxiolytic drug”Clinical Pharmacokinetics36 (4): 277–87. doi:10.2165/00003088-199936040-00003PMID 10320950S2CID 1102318.
  8. Jump up to:a b c d Zhu M, Zhao W, Jimenez H, Zhang D, Yeola S, Dai R, et al. (April 2005). “Cytochrome P450 3A-mediated metabolism of buspirone in human liver microsomes”. Drug Metabolism and Disposition33 (4): 500–7. doi:10.1124/dmd.104.000836PMID 15640381S2CID 10142905.
  9. Jump up to:a b c d e f “Buspirone Hydrochloride Monograph for Professionals”Drugs.com. American Society of Health-System Pharmacists. Retrieved 3 March 2019.
  10. Jump up to:a b c d Wilson, T. K.; Tripp, J. (January 2018). “Buspirone”StatPearlsPMID 30285372.
  11. Jump up to:a b c d e British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 338. ISBN 9780857113382.
  12. ^ “Buspirone Pregnancy and Breastfeeding Warnings”Drugs.com. Retrieved 3 March 2019.
  13. ^ “The Top 300 of 2021”ClinCalc. Retrieved 18 February 2021.
  14. ^ “Buspirone Hydrochloride – Drug Usage Statistics”ClinCalc. Retrieved 18 February 2021.
  15. Jump up to:a b “BUSPIRONE HCL (buspirone hydrochloride) tablet [Watson Laboratories, Inc.]”DailyMed. Watson Laboratories, Inc. July 2013. Retrieved 14 November 2013.
  16. Jump up to:a b c “BUSPAR® (buspirone hydrochloride) Tablets 5 mg & 10 mg PRODUCT INFORMATION” (PDF)TGA eBusiness Services. Aspen Pharma Pty Ltd. January 2010. Retrieved 14 November2013.
  17. ^ Rossi S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  18. Jump up to:a b “Buspirone 10mg Tablets”electronic Medicines Compendium. Actavis UK Ltd. 10 September 2012. Retrieved 14 November 2013.
  19. ^ Joint Formulary Committee. British National Formulary (BNF). Pharmaceutical Press. p. 224.
  20. Jump up to:a b Sadock BJ, Sadock VA, Ruiz P (22 September 2014). Kaplan and Sadock’s Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry. Wolters Kluwer Health. pp. 3211–. ISBN 978-1-4698-8375-5.
  21. Jump up to:a b c Howland RH (November 2015). “Buspirone: Back to the Future”. Journal of Psychosocial Nursing and Mental Health Services53 (11): 21–4. doi:10.3928/02793695-20151022-01PMID 26535760.
  22. ^ Masdrakis VG, Turic D, Baldwin DS (2013). “Pharmacological treatment of social anxiety disorder”. Anxiety Disorders. Modern Trends in Pharmacopsychiatry. 29. pp. 144–53. doi:10.1159/000351960ISBN 978-3-318-02463-0PMID 25225024.
  23. ^ Goldstein I, Kim NN, Clayton AH, DeRogatis LR, Giraldi A, Parish SJ, et al. (January 2017). “Hypoactive Sexual Desire Disorder: International Society for the Study of Women’s Sexual Health (ISSWSH) Expert Consensus Panel Review”Mayo Clinic Proceedings92 (1): 114–128. doi:10.1016/j.mayocp.2016.09.018PMID 27916394.
  24. ^ Sontheimer DL, Ables AZ (March 2001). “Is imipramine or buspirone treatment effective in patients wishing to discontinue long-term benzodiazepine use?”. The Journal of Family Practice50(3): 203. PMID 11252203.
  25. ^ Garrett AR, Hawley JS (April 2018). “SSRI-associated bruxism: A systematic review of published case reports”Neurology. Clinical Practice8 (2): 135–141. doi:10.1212/CPJ.0000000000000433PMC 5914744PMID 29708207.
  26. ^ Prisco V, Iannaccone T, Di Grezia G (2017-04-01). “Use of buspirone in selective serotonin reuptake inhibitor-induced sleep bruxism”. European Psychiatry. Abstract of the 25th European Congress of Psychiatry. 41: S855. doi:10.1016/j.eurpsy.2017.01.1701.
  27. Jump up to:a b c “Buspirone monograph”. Drugs.com. Retrieved 2011-08-27.
  28. ^ Geddes J, Gelder MG, Mayou R (2005). Psychiatry. Oxford [Oxfordshire]: Oxford University Press. p. 237ISBN 978-0-19-852863-0.
  29. ^ Fulton B, Brogden RN (1997). “Buspirone”. CNS Drugs7 (1): 68–88. doi:10.2165/00023210-199707010-00007ISSN 1172-7047.
  30. Jump up to:a b c Dart RC (2004). Medical Toxicology. Lippincott Williams & Wilkins. pp. 886–. ISBN 978-0-7817-2845-4.
  31. ^ Lilja JJ, Kivistö KT, Backman JT, Lamberg TS, Neuvonen PJ (December 1998). “Grapefruit juice substantially increases plasma concentrations of buspirone”. Clinical Pharmacology and Therapeutics64 (6): 655–60. doi:10.1016/S0009-9236(98)90056-XPMID 9871430S2CID 22009095.
  32. ^ Lamberg TS, Kivistö KT, Laitila J, Mårtensson K, Neuvonen PJ (1998). “The effect of fluvoxamine on the pharmacokinetics and pharmacodynamics of buspirone”. European Journal of Clinical Pharmacology54 (9–10): 761–6. doi:10.1007/s002280050548PMID 9923581S2CID 21939719.
  33. Jump up to:a b c Roth BL, Driscol J. “PDSP Ki Database”Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
  34. ^ Boess FG, Martin IL (1994). “Molecular biology of 5-HT receptors”. Neuropharmacology33 (3–4): 275–317. doi:10.1016/0028-3908(94)90059-0PMID 7984267S2CID 35553281.
  35. Jump up to:a b c d e f g h i j k l m Hamik A, Oksenberg D, Fischette C, Peroutka SJ (July 1990). “Analysis of tandospirone (SM-3997) interactions with neurotransmitter receptor binding sites”. Biological Psychiatry28 (2): 99–109. doi:10.1016/0006-3223(90)90627-ePMID 1974152S2CID 25608914.
  36. ^ Peroutka SJ, Switzer JA, Hamik A (1989). “Identification of 5-hydroxytryptamine1D binding sites in human brain membranes”. Synapse3 (1): 61–6. doi:10.1002/syn.890030109PMID 2521959.
  37. ^ Waeber C, Schoeffter P, Palacios JM, Hoyer D (June 1988). “Molecular pharmacology of 5-HT1D recognition sites: radioligand binding studies in human, pig and calf brain membranes”. Naunyn-Schmiedeberg’s Archives of Pharmacology337 (6): 595–601. doi:10.1007/bf00175783PMID 2975354S2CID 21344978.
  38. Jump up to:a b c d e Bonhaus DW, Weinhardt KK, Taylor M, DeSouza A, McNeeley PM, Szczepanski K, et al. (1997). “RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist”. Neuropharmacology36 (4–5): 621–9. doi:10.1016/s0028-3908(97)00049-xPMID 9225287S2CID 24930608.
  39. ^ Nelson DR, Thomas DR (May 1989). “[3H]-BRL 43694 (Granisetron), a specific ligand for 5-HT3 binding sites in rat brain cortical membranes”. Biochemical Pharmacology38 (10): 1693–5. doi:10.1016/0006-2952(89)90319-5PMID 2543418.
  40. Jump up to:a b Borsini F, Giraldo E, Monferini E, Antonini G, Parenti M, Bietti G, Donetti A (September 1995). “BIMT 17, a 5-HT2A receptor antagonist and 5-HT1A receptor full agonist in rat cerebral cortex”. Naunyn-Schmiedeberg’s Archives of Pharmacology352 (3): 276–82. doi:10.1007/bf00168557PMID 8584042S2CID 19340842.
  41. ^ Plassat JL, Amlaiky N, Hen R (August 1993). “Molecular cloning of a mammalian serotonin receptor that activates adenylate cyclase”. Molecular Pharmacology44 (2): 229–36. PMID 8394987.
  42. ^ Lovenberg TW, Baron BM, de Lecea L, Miller JD, Prosser RA, Rea MA, et al. (September 1993). “A novel adenylyl cyclase-activating serotonin receptor (5-HT7) implicated in the regulation of mammalian circadian rhythms”. Neuron11 (3): 449–58. doi:10.1016/0896-6273(93)90149-lPMID 8398139S2CID 28729004.
  43. ^ Ruat M, Traiffort E, Leurs R, Tardivel-Lacombe J, Diaz J, Arrang JM, Schwartz JC (September 1993). “Molecular cloning, characterization, and localization of a high-affinity serotonin receptor (5-HT7) activating cAMP formation”Proceedings of the National Academy of Sciences of the United States of America90 (18): 8547–51. Bibcode:1993PNAS…90.8547Rdoi:10.1073/pnas.90.18.8547PMC 47394PMID 8397408.
  44. Jump up to:a b Blier P, Curet O, Chaput Y, de Montigny C (July 1991). “Tandospirone and its metabolite, 1-(2-pyrimidinyl)-piperazine–II. Effects of acute administration of 1-PP and long-term administration of tandospirone on noradrenergic neurotransmission”. Neuropharmacology30 (7): 691–701. doi:10.1016/0028-3908(91)90176-cPMID 1681447S2CID 44297577.
  45. Jump up to:a b c d Bergman J, Roof RA, Furman CA, Conroy JL, Mello NK, Sibley DR, Skolnick P (March 2013). “Modification of cocaine self-administration by buspirone (buspar®): potential involvement of D3 and D4 dopamine receptors”The International Journal of Neuropsychopharmacology16 (2): 445–58. doi:10.1017/S1461145712000661PMC 5100812PMID 22827916.
  46. Jump up to:a b c Tunnicliff G (September 1991). “Molecular basis of buspirone’s anxiolytic action”. Pharmacology & Toxicology69 (3): 149–56. doi:10.1111/j.1600-0773.1991.tb01289.xPMID 1796057.
  47. ^ Zuideveld KP, Rusiç-Pavletiç J, Maas HJ, Peletier LA, Van der Graaf PH, Danhof M (December 2002). “Pharmacokinetic-pharmacodynamic modeling of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine in rats”. The Journal of Pharmacology and Experimental Therapeutics303 (3): 1130–7. doi:10.1124/jpet.102.036798PMID 12438536S2CID 14139919.
  48. Jump up to:a b c Fava M (2007). “The combination of buspirone and bupropion in the treatment of depression”. Psychotherapy and Psychosomatics76 (5): 311–2. doi:10.1159/000104708PMID 17700052S2CID 46284917.
  49. Jump up to:a b Stern TA, Fava M, Wilens TE, Rosenbaum JF (27 April 2015). Massachusetts General Hospital Psychopharmacology and Neurotherapeutics E-Book. Elsevier Health Sciences. pp. 29–. ISBN 978-0-323-41323-7.
  50. ^ Nutt DJ, Ballenger JC (15 April 2008). Anxiety Disorders. John Wiley & Sons. pp. 395–. ISBN 978-0-470-98683-7.
  51. ^ Dockens RC, Salazar DE, Fulmor IE, Wehling M, Arnold ME, Croop R (November 2006). “Pharmacokinetics of a newly identified active metabolite of buspirone after administration of buspirone over its therapeutic dose range”. Journal of Clinical Pharmacology46(11): 1308–12. doi:10.1177/0091270006292250PMID 17050795.
  52. ^ Jajoo HK, Mayol RF, LaBudde JA, Blair IA (1989). “Metabolism of the antianxiety drug buspirone in human subjects”. Drug Metabolism and Disposition17 (6): 634–40. PMID 2575499.
  53. ^ Taylor DP, Moon SL (July 1991). “Buspirone and related compounds as alternative anxiolytics”. Neuropeptides. 19 Suppl: 15–9. doi:10.1016/0143-4179(91)90078-wPMID 1679210S2CID 13730683.
  54. Jump up to:a b Allen LE, Ferguson HC, Kissel JW (May 1972). “Psychosedative agents. 2. 8-(4-Substituted 1-piperazinylalkyl)-8-azaspiro(4.5)decane-7,9-diones”. Journal of Medicinal Chemistry15 (5): 477–9. doi:10.1021/jm00275a009PMID 5035267.
  55. ^ US Patent 3907801 N-(8 (4-pyridyl-piperazino)-alkyl(9 -azaspiroalkanediones
  56. ^ United States Federal Drug Administration (September 9, 1986). Approval Type-1 New Molecular Entry.https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/018731Orig1s000rev.pdf
  57. Jump up to:a b Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 149–. ISBN 978-3-88763-075-1.
  58. ^ Morton IK, Hall JM (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 57–. ISBN 978-94-011-4439-1.
  59. Jump up to:a b “Buspirone”.
  60. ^ “Drugs@FDA: FDA Approved Drug Products”www.accessdata.fda.gov. Retrieved 2019-09-20.
  61. ^ “Determination That BUSPAR (Buspirone Hydrochloride) Tablets, 10 Milligrams, 15 Milligrams, and 30 Milligrams, Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness”Federal Register. 2010-10-19. Retrieved 2019-09-20.
  62. ^ Rabin RC (2019-02-01). “Shortage of Anxiety Drug Leaves Patients Scrambling”The New York TimesISSN 0362-4331. Retrieved 2019-09-20.

External links

  •  Media related to Buspirone at Wikimedia Commons
  • “Buspirone”Drug Information Portal. U.S. National Library of Medicine.
Buspirone
Buspirone 200.svg
Clinical data
Pronunciation /ˈbjuːspɪrn/ (BEW-spi-rohn)
Trade names Buspar, Namanspin
Other names MJ 9022-1[1]
AHFS/Drugs.com Monograph
MedlinePlus a688005
Pregnancy
category
  • AU: B1
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 3.9%[2]
Protein binding 86–95%[3]
Metabolism Liver (via CYP3A4)[7][8]
Metabolites 5-OH-Buspirone; 6-OH-Buspirone; 8-OH-Buspirone; 1-PP[4][5][6]
Elimination half-life 2.5 hours[7]
Excretion Urine: 29–63%[3]
Feces: 18–38%[3]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.048.232 Edit this at Wikidata
Chemical and physical data
Formula C21H31N5O2
Molar mass 385.512 g·mol−1
3D model (JSmol)

hide

  • O=C1N(CCCCN2CCN(CC2)C3=NC=CC=N3)C(CC4(CCCC4)C1)=O

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  • InChI=1S/C21H31N5O2/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 check
  • Key:QWCRAEMEVRGPNT-UHFFFAOYSA-N check

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#Buspirone, #буспирон , #بوسبيرون , #丁螺酮 , #Anxiolytic, #Arylpiperazines,  #Serotonin Receptor Agonist, #Ansial, #Vita,  #Ansiced,  #Abello,  #Axoren, #Glaxo Wellcome,  #Bespar, #BMS,  #Buspar, #Buspimen, Menarini,  Buspinol, Zdravlje,  Buspisal, Lesvi,  Narol, Almirall,

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