Chemistry:Buspirone

From HandWiki
Short description: Medication used to treat anxiety disorders
Buspirone
Buspirone 200.svg
Buspirone 3D structure.png
Clinical data
Pronunciation/ˈbjuːspɪroʊn/ (BEW-spi-rohn)
Trade namesBuspar, Namanspin
Other namesMJ 9022-1[1]
AHFS/Drugs.comMonograph
MedlinePlusa688005
License data
Pregnancy
category
  • AU: B1
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability3.9%[2]
Protein binding86–95%[3]
MetabolismLiver (via CYP3A4)[7][8]
Metabolites5-OH-Buspirone; 6-OH-Buspirone; 8-OH-Buspirone; 1-PP[4][5][6]
Elimination half-life2.5 hours[7]
ExcretionUrine: 29–63%[3]
Feces: 18–38%[3]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC21H31N5O2
Molar mass385.512 g·mol−1
3D model (JSmol)
  (verify)


Buspirone, sold under the brand name Buspar, among others, is an anxiolytic, a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder.[9][10] It is a serotonin 5-HT1A receptor agonist, increasing action at serotonin receptors in the brain.[2] It is taken orally, and takes two to six weeks to be fully effective.[9][10]

Common side effects of buspirone include nausea, headaches, dizziness, and difficulty concentrating.[9][11] Serious side effects may include movement disorders, serotonin syndrome, and seizures.[11] Its use in pregnancy appears to be safe but has not been well studied, and use during breastfeeding has not been well studied.[11][12]

Buspirone was developed in 1968 and approved for medical use in the United States in 1986.[9][10] It is available as a generic medication.[11] In 2021, it was the 53rd most-commonly prescribed medication in the United States, with more than 12 million prescriptions.[13][14]

Medical uses

Anxiety

Buspirone is used for the short-term and long-term treatment of anxiety disorders or symptoms of anxiety.[15][16][17][18][19] It is generally preferred over benzodiazepines because it does not activate the receptors that make drugs like alprazolam addictive.[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 diazepam, alprazolam, lorazepam, 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] Buspirone may also be effective in treating antidepressant-induced sexual dysfunction.[10][24][25]

Miscellaneous

Buspirone is not effective as a treatment for benzodiazepine withdrawal, barbiturate withdrawal, or alcohol withdrawal/delirium tremens.[26]

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.[27][28]

Contraindications

Buspirone has these contraindications:[29][30]

  • Hypersensitivity to buspirone
  • Metabolic acidosis, as in diabetes
  • Should not be used with MAO inhibitors
  • Severely compromised liver and/or kidney function

Side effects

Known side effects associated with buspirone include dizziness, headaches, nausea, tinnitus, and paresthesia.[2] Buspirone is relatively well tolerated, and is not associated with sedation, cognitive and psychomotor impairment, muscle relaxation, physical dependence, or anticonvulsant effects.[2] In addition, buspirone does not produce euphoria[20] and is not a drug of abuse.[16] Dyskinesia, akathisia, myoclonus, parkinsonism, and dystonia were reported associated with buspirone.[31] 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.[32] In one clinical trial, buspirone was administered to healthy male volunteers at a dosage of 375 mg/day, and produced side effects including nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress.[15][16][18] In early clinical trials, buspirone was given at dosages even as high as 2,400 mg/day, with akathisia, tremor, and muscle rigidity observed.[33] Deliberate overdoses with 250 mg and up to 300 mg buspirone have resulted in drowsiness in about 50% of individuals.[33] One death has been reported in a co-ingestion of 450 mg buspirone with alprazolam, diltiazem, alcohol, cocaine.[33]

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:[29]

Elevated blood pressure has been reported when buspirone has been administered to patients taking monoamine oxidase inhibitors (MAOIs).[29]

Pharmacology

Pharmacodynamics

Site Ki (nM) Action Species Ref
5-HT1A 3.98–214
21 (median) 		Agonist Human [36][37]
5-HT1B >100,000 Agonist ? [38] Rat [39]
5-HT1D 22,000–42,700 Agonist ? [38] Human [40][41]
5-HT2C 1,100–6,026 Antagonist ? [38] Rat/pig
[39]
5-HT7 375–381
840 		Antagonist ? [38] Rat
Human		 [42][43]
[44]
α1 1,000 Antagonist Rat [39]
α2 6,000 Antagonist Rat [45]
  α2A 7.3 (1-PP) Antagonist Human [39]
β 8,800 Antagonist Rat [39]
D1 33,000 Antagonist Rat [39]
D2 484
240 		Antagonist Human
Rat		 [46]
[39]
D3 98 Antagonist Human [46]
D4 29 Antagonist Human [46]
mACh 38,000 ? Rat [39]
GABAA
(BDZ)		 >100,000 - Rat [39]
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][39] 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 seems to have lower affinities for the serotonin 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, 5-HT7 receptors probably as an antagonist.[38]

In addition to binding to serotonin receptors, buspirone is an antagonist of the dopamine D2 receptor with weak affinity.[2][39] 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.[46]

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.[45][47][48] This metabolite may be responsible for the increased noradrenergic and dopaminergic activity observed with buspirone in animals.[47][49] In addition, 1-PP may play an important role in the antidepressant effects of buspirone.[49] Buspirone also has very weak and probably clinically unimportant affinity for the α1-adrenergic receptor.[39][50] 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".[50]

Unlike benzodiazepines, buspirone does not interact with the GABAA receptor complex.[2][51]

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.[52][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.[47][49]

Phase I Metabolism of buspirone in humans[53][54][55][8]

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 gepirone, ipsapirone, perospirone, and tandospirone.[56]

A number of analogues are recorded.[57]

Synthesis

A number of more modern methods of synthesis have also been reported (list not exhaustive):[58][59][60]

Error creating thumbnail: Unable to save thumbnail to destination
Synthesis:[61] Patents:[62][63][64] Polymorphic crystalline form:[65]

Alkylation of 1-(2-pyrimidyl)piperazine [20980-22-7] (1) with 3-chloro-1-cyanopropane (4-chlorobutyronitrile) [628-20-6] (2) gives [33386-14-0] (3). the reduction of the nitrile group is performed either by catalytic hydrogenation or with LAH giving [33386-20-8] (4). The primary amine is then reacted with 3,3-tetramethyleneglutaric anhydride [5662-95-3] (5) in order to yield Buspirone (6).

History

Buspirone was first synthesized by a team at Mead Johnson in 1968[21] but was not patented until 1980.[66][61][67] It was initially developed as an antipsychotic 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][68] The patent expired in 2001, and buspirone is now available as a generic drug.

Society and culture

Buspar (buspirone) 10-mg tablets

Generic names

Buspirone is the INN, BAN, DCF, and DCIT of buspirone, while buspirone hydrochloride is its USAN, BANM, and JAN.[1][69][70][71]

Brand names

Buspirone was primarily sold under the brand name Buspar.[69][71] Buspar is currently listed as discontinued by the US Food and Drug Administration.[72] In 2010, in response to a citizen petition, the US FDA determined that Buspar was not withdrawn from sale for reasons of safety or effectiveness.[73]

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.[74]

References

  1. ↑ 1.0 1.1 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. pp. 192–. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA192. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 "Buspirone: what is it all about?". Brain Research 1461: 111–118. June 2012. doi:10.1016/j.brainres.2012.04.032. PMID 22608068. 
  3. ↑ 3.0 3.1 3.2 "buspirone (Rx) - BuSpar, Buspirex, more..". Medscape Reference. WebMD. http://reference.medscape.com/drug/buspar-buspirone-342913. 
  4. ↑ 4.0 4.1 4.2 "Metabolism and disposition of buspirone". The American Journal of Medicine 80 (3B): 41–51. March 1986. doi:10.1016/0002-9343(86)90331-1. PMID 3515929. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 The American Psychiatric Publishing Textbook of Psychopharmacology. American Psychiatric Pub. 2009. pp. 490–. ISBN 978-1-58562-309-9. https://books.google.com/books?id=Xx7iNGdV25IC&pg=PA490. 
  6. ↑ 6.0 6.1 "6-Hydroxybuspirone is a major active metabolite of buspirone: assessment of pharmacokinetics and 5-hydroxytryptamine1A receptor occupancy in rats". Drug Metabolism and Disposition 35 (8): 1387–1392. August 2007. doi:10.1124/dmd.107.015768. PMID 17494642. 
  7. ↑ 7.0 7.1 7.2 "Clinical pharmacokinetics and pharmacodynamics of buspirone, an anxiolytic drug". Clinical Pharmacokinetics 36 (4): 277–287. April 1999. doi:10.2165/00003088-199936040-00003. PMID 10320950. https://zenodo.org/record/1236411. 
  8. ↑ 8.0 8.1 8.2 8.3 "Cytochrome P450 3A-mediated metabolism of buspirone in human liver microsomes". Drug Metabolism and Disposition 33 (4): 500–507. April 2005. doi:10.1124/dmd.104.000836. PMID 15640381. 
  9. ↑ 9.0 9.1 9.2 9.3 9.4 "Buspirone Hydrochloride Monograph for Professionals". https://www.drugs.com/monograph/buspirone.html. 
  10. ↑ 10.0 10.1 10.2 10.3 10.4 "Buspirone". StatPearls. January 2018. PMID 30285372. https://www.ncbi.nlm.nih.gov/books/NBK531477/. 
  11. ↑ 11.0 11.1 11.2 11.3 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 338. ISBN 9780857113382. 
  12. ↑ "Buspirone Pregnancy and Breastfeeding Warnings". https://www.drugs.com/pregnancy/buspirone.html. 
  13. ↑ "The Top 300 of 2021". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  14. ↑ "Buspirone - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Buspirone. 
  15. ↑ 15.0 15.1 "BUSPIRONE HCL (buspirone hydrochloride) tablet [Watson Laboratories, Inc."]. DailyMed. Watson Laboratories, Inc.. July 2013. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a3fe0ccd-565f-4d0a-a7ba-2fad7a819358. 
  16. ↑ 16.0 16.1 16.2 "BUSPAR® (buspirone hydrochloride) Tablets 5 mg & 10 mg PRODUCT INFORMATION" (PDF). TGA eBusiness Services. Aspen Pharma Pty Ltd. January 2010. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03962-3. 
  17. ↑ Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. 2013. ISBN 978-0-9805790-9-3. 
  18. ↑ 18.0 18.1 "Buspirone 10mg Tablets". electronic Medicines Compendium. Actavis UK Ltd. 10 September 2012. http://www.medicines.org.uk/emc/medicine/23859/SPC/Buspirone+10mg+Tablets/. 
  19. ↑ Joint Formulary Committee. British National Formulary (BNF). Pharmaceutical Press. pp. 224. 
  20. ↑ 20.0 20.1 Kaplan and Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry. Wolters Kluwer Health. 22 September 2014. pp. 3211–. ISBN 978-1-4698-8375-5. https://books.google.com/books?id=IzGYBAAAQBAJ&pg=PT3211. 
  21. ↑ 21.0 21.1 21.2 "Buspirone: Back to the Future". Journal of Psychosocial Nursing and Mental Health Services 53 (11): 21–24. November 2015. doi:10.3928/02793695-20151022-01. PMID 26535760. 
  22. ↑ "Pharmacological treatment of social anxiety disorder". Anxiety Disorders. Modern Trends in Pharmacopsychiatry. 29. 2013. pp. 144–53. doi:10.1159/000351960. ISBN 978-3-318-02463-0. 
  23. ↑ "Hypoactive Sexual Desire Disorder: International Society for the Study of Women's Sexual Health (ISSWSH) Expert Consensus Panel Review". Mayo Clinic Proceedings 92 (1): 114–128. January 2017. doi:10.1016/j.mayocp.2016.09.018. PMID 27916394. 
  24. ↑ "Erectile and Ejaculatory Dysfunction Associated with Use of Psychotropic Drugs: A Systematic Review". The Journal of Sexual Medicine 18 (8): 1354–1363. August 2021. doi:10.1016/j.jsxm.2021.05.016. PMID 34247952. "Buspirone, a non-benzodiazepine anxiolytic, have even demonstrated enhancement of sexual function in certain individuals. For this reason, they have been proposed as augmentation agents (antidotes) or substitution agents in patients with emerging sexual dysfunction after treatment with antidepressants.". 
  25. ↑ "Management Strategies for Antidepressant-Related Sexual Dysfunction: A Clinical Approach". Journal of Clinical Medicine 8 (10): 1640. October 2019. doi:10.3390/jcm8101640. PMID 31591339. 
  26. ↑ "Is imipramine or buspirone treatment effective in patients wishing to discontinue long-term benzodiazepine use?". The Journal of Family Practice 50 (3): 203. March 2001. PMID 11252203. 
  27. ↑ "SSRI-associated bruxism: A systematic review of published case reports". Neurology. Clinical Practice 8 (2): 135–141. April 2018. doi:10.1212/CPJ.0000000000000433. PMID 29708207. 
  28. ↑ "Use of buspirone in selective serotonin reuptake inhibitor-induced sleep bruxism". European Psychiatry. Abstract of the 25th European Congress of Psychiatry 41: S855. 1 April 2017. doi:10.1016/j.eurpsy.2017.01.1701. 
  29. ↑ 29.0 29.1 29.2 "Buspirone monograph". Drugs.com. https://www.drugs.com/pro/buspirone.html. 
  30. ↑ Psychiatry. Oxford [Oxfordshire]: Oxford University Press. 2005. p. 237. ISBN 978-0-19-852863-0. https://archive.org/details/psychiatry0000geld/page/237. 
  31. ↑ "Buspirone-associated Movement Disorder: A Literature Review". Prague Medical Report 121 (1): 5–24. 2020. doi:10.14712/23362936.2020.1. PMID 32191616. 
  32. ↑ "Buspirone". CNS Drugs 7 (1): 68–88. 1997. doi:10.2165/00023210-199707010-00007. ISSN 1172-7047. 
  33. ↑ 33.0 33.1 33.2 Medical Toxicology. Lippincott Williams & Wilkins. 2004. pp. 886–. ISBN 978-0-7817-2845-4. https://books.google.com/books?id=BfdighlyGiwC&pg=PA886. 
  34. ↑ "Grapefruit juice substantially increases plasma concentrations of buspirone". Clinical Pharmacology and Therapeutics 64 (6): 655–660. December 1998. doi:10.1016/S0009-9236(98)90056-X. PMID 9871430. 
  35. ↑ "The effect of fluvoxamine on the pharmacokinetics and pharmacodynamics of buspirone". European Journal of Clinical Pharmacology 54 (9–10): 761–766. 1998. doi:10.1007/s002280050548. PMID 9923581. 
  36. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named PDSP
  37. ↑ "Molecular biology of 5-HT receptors". Neuropharmacology 33 (3–4): 275–317. 1994. doi:10.1016/0028-3908(94)90059-0. PMID 7984267. 
  38. ↑ 38.0 38.1 38.2 38.3 38.4 "Chronic buspirone treatment decreases 5-HT1B receptor densities and the serotonin transporter but increases the density of 5-HT2A receptors in the bulbectomized rat model of depression: an autoradiographic study". Brain Research 1345: 28–44. July 2010. doi:10.1016/j.brainres.2010.05.054. PMID 20501324. 
  39. ↑ 39.00 39.01 39.02 39.03 39.04 39.05 39.06 39.07 39.08 39.09 39.10 39.11 "Analysis of tandospirone (SM-3997) interactions with neurotransmitter receptor binding sites". Biological Psychiatry 28 (2): 99–109. July 1990. doi:10.1016/0006-3223(90)90627-e. PMID 1974152. 
  40. ↑ "Identification of 5-hydroxytryptamine1D binding sites in human brain membranes". Synapse 3 (1): 61–66. 1989. doi:10.1002/syn.890030109. PMID 2521959. 
  41. ↑ "Molecular pharmacology of 5-HT1D recognition sites: radioligand binding studies in human, pig and calf brain membranes". Naunyn-Schmiedeberg's Archives of Pharmacology 337 (6): 595–601. June 1988. doi:10.1007/bf00175783. PMID 2975354. 
  42. ↑ "A novel adenylyl cyclase-activating serotonin receptor (5-HT7) implicated in the regulation of mammalian circadian rhythms". Neuron 11 (3): 449–458. September 1993. doi:10.1016/0896-6273(93)90149-l. PMID 8398139. 
  43. ↑ "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 America 90 (18): 8547–8551. September 1993. doi:10.1073/pnas.90.18.8547. PMID 8397408. Bibcode: 1993PNAS...90.8547R. 
  44. ↑ "Synthesis of novel 5-substituted-2-aminotetralin analogs: 5-HT1A and 5-HT7 G protein-coupled receptor affinity, 3D-QSAR and molecular modeling". Bioorganic & Medicinal Chemistry 28 (3): 115262. February 2020. doi:10.1016/j.bmc.2019.115262. PMID 31882369. 
  45. ↑ 45.0 45.1 "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". Neuropharmacology 30 (7): 691–701. July 1991. doi:10.1016/0028-3908(91)90176-c. PMID 1681447. 
  46. ↑ 46.0 46.1 46.2 46.3 "Modification of cocaine self-administration by buspirone (buspar®): potential involvement of D3 and D4 dopamine receptors". The International Journal of Neuropsychopharmacology 16 (2): 445–458. March 2013. doi:10.1017/S1461145712000661. PMID 22827916. 
  47. ↑ 47.0 47.1 47.2 "Molecular basis of buspirone's anxiolytic action". Pharmacology & Toxicology 69 (3): 149–156. September 1991. doi:10.1111/j.1600-0773.1991.tb01289.x. PMID 1796057. 
  48. ↑ "Pharmacokinetic-pharmacodynamic modeling of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine in rats". The Journal of Pharmacology and Experimental Therapeutics 303 (3): 1130–1137. December 2002. doi:10.1124/jpet.102.036798. PMID 12438536. 
  49. ↑ 49.0 49.1 49.2 "The combination of buspirone and bupropion in the treatment of depression". Psychotherapy and Psychosomatics 76 (5): 311–312. 2007. doi:10.1159/000104708. PMID 17700052. 
  50. ↑ 50.0 50.1 Massachusetts General Hospital Psychopharmacology and Neurotherapeutics E-Book. Elsevier Health Sciences. 27 April 2015. pp. 29–. ISBN 978-0-323-41323-7. https://books.google.com/books?id=CCZ1CQAAQBAJ&pg=PA29. 
  51. ↑ Anxiety Disorders. John Wiley & Sons. 15 April 2008. pp. 395–. ISBN 978-0-470-98683-7. https://books.google.com/books?id=swAE2bRjV8UC&pg=PT395. 
  52. ↑ "High-Throughput Metabolic Soft-Spot Identification in Liver Microsomes by LC/UV/MS: Application of a Single Variable Incubation Time Approach". Molecules 27 (22): 8058. November 2022. doi:10.3390/molecules27228058. PMID 36432161. 
  53. ↑ "High-Throughput Metabolic Soft-Spot Identification in Liver Microsomes by LC/UV/MS: Application of a Single Variable Incubation Time Approach". Molecules 27 (22): 8058. November 2022. doi:10.3390/molecules27228058. PMID 36432161. 
  54. ↑ "Pharmacokinetics of a newly identified active metabolite of buspirone after administration of buspirone over its therapeutic dose range". Journal of Clinical Pharmacology 46 (11): 1308–1312. November 2006. doi:10.1177/0091270006292250. PMID 17050795. 
  55. ↑ "Metabolism of the antianxiety drug buspirone in human subjects". Drug Metabolism and Disposition 17 (6): 634–640. 1989. PMID 2575499. 
  56. ↑ "Buspirone and related compounds as alternative anxiolytics". Neuropeptides 19 (Suppl): 15–19. July 1991. doi:10.1016/0143-4179(91)90078-w. PMID 1679210. 
  57. ↑ "Buspirone analogues. 1. Structure-activity relationships in a series of N-aryl- and heteroarylpiperazine derivatives". Journal of Medicinal Chemistry 26 (2): 194–203. February 1983. doi:10.1021/jm00356a014. PMID 6131130. 
  58. ↑ "An Efficient Synthesis of Buspirone and its Analogues.". Archiv der Pharmazie 325 (5): 313–315. 1992. doi:10.1002/ardp.19923250513. 
  59. ↑ "Pd(0)-catalysed Synthesis of Buspirone and Gepirone.". Heterocycles 36 (7): 1463–1469. 1993. doi:10.3987/COM-93-6357. 
  60. ↑ "Facile Synthesis of Anxiolytic Buspirone". Organic Preparations and Procedures International 40 (4): 391–394. August 2008. doi:10.1080/00304940809458099. ISSN 0030-4948. 
  61. ↑ 61.0 61.1 "Psychosedative agents. 2. 8-(4-Substituted 1-piperazinylalkyl)-8-azaspiro(4.5)decane-7,9-diones". Journal of Medicinal Chemistry 15 (5): 477–479. May 1972. doi:10.1021/jm00275a009. PMID 5035267. 
  62. ↑ DE2057845 idem Y Wu, J Rayburn, U.S. Patent 3,717,634 (1973 to Mead Johnson).
  63. ↑ Wu YH, Rayburn JW, US patent 3907801, issued 1975, assigned to Mead Johnson
  64. ↑ Wu YH, Rayburn JW, US patent 3976776, issued 1976, assigned to Mead Johnson
  65. ↑ Behme RJ, Kensler TT, Mikolasek DG, US patent 4810789, issued 1989, assigned to Bristol Myers
  66. ↑ Casten GP, McKinney GR, Newton RE, Tompkins EC, Weikel Jr JH, "Buspirone anti-anxiety method", US patent 4182763, published 1980-01-08, assigned to Mead Johnson & Co.and Bristol-Meyers Co.
  67. ↑ Hua WY, Warren RJ, "N-[(4-pyridyl-piperazino)-alkyl]-azaspiroalkanediones", US patent 3907801, published 1975-09-23
  68. ↑ "Approval Type-1 New Molecular Entry.". United States Federal Drug Administration. 9 September 1986. https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/018731Orig1s000rev.pdf. 
  69. ↑ 69.0 69.1 Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 149–. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA149. 
  70. ↑ Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. 6 December 2012. pp. 57–. ISBN 978-94-011-4439-1. https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA57. 
  71. ↑ 71.0 71.1 "Buspirone". Drugs.com. https://www.drugs.com/international/buspirone.html. 
  72. ↑ "Drugs@FDA: FDA Approved Drug Products". Food and Drug Administration. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=018731. 
  73. ↑ "Determination That BUSPAR (Buspirone Hydrochloride) Tablets, 10 Milligrams, 15 Milligrams, and 30 Milligrams, Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness". 19 October 2010. https://www.federalregister.gov/documents/2010/10/19/2010-26214/determination-that-buspar-buspirone-hydrochloride-tablets-10-milligrams-15-milligrams-and-30. 
  74. ↑ "Shortage of Anxiety Drug Leaves Patients Scrambling" (in en-US). The New York Times. 1 February 2019. ISSN 0362-4331. https://www.nytimes.com/2019/02/01/well/mind/anxiety-drug-shortage-buspirone.html. 

External links

{{Navbox 

| name = Sexual dysfunction pharmacotherapies
| title = Sexual dysfunction pharmacotherapies
| state = autocollapse
| bodyclass = hlist
| listclass = hlist

| group1 = Dopamine agonists
| list1 =

| group2 = Melanocortin agonists
| list2 =

| group3 = PDE5 inhibitors
| list3 =

| group4 = Sex steroids
| list4 =

| group5 = Others
| list5 =

| below =

}}



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Buspirone&oldid=3711221"