Buspirone was first made in 1968 and approved for medical use in the United States in 1986. It is available as a generic medication. In 2020, it was the 55th most-commonly prescribed medication in the United States, with more than 12million prescriptions.
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.
Buspirone has been shown in vitro to be metabolized by the enzymeCYP3A4. This finding is consistent with the in vivo interactions observed between buspirone and these inhibitors or inducers of cytochrome P450 3A4 (CYP3A4), among others:
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. This metabolite may be responsible for the increased noradrenergic and dopaminergic activity observed with buspirone in animals. In addition, 1-PP may play an important role in the antidepressant effects of buspirone. Buspirone also has very weak and probably clinically unimportant affinity for the α1-adrenergic receptor. 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".
Buspirone has a low oralbioavailability of 3.9% relative to intravenous injection due to extensive first-pass metabolism. The time to peak plasma levels following ingestion is 0.9 to 1.5 hours. It is reported to have an elimination half-life of 2.8 hours, 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. Buspirone is metabolized primarily by CYP3A4, and prominent drug interactions with inhibitors and inducers of this enzyme have been observed. Major metabolites of buspirone include 5-hydroxybuspirone, 6-hydroxybuspirone, 8-hydroxybuspirone, and 1-PP. 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. 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. As such, it is likely to play an important role in the therapeutic effects of buspirone. 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.
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).
Buspirone was primarily sold under the brand name Buspar. Buspar is currently listed as discontinued by the US Federal Drug Administration. 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.
^ abWong 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 Disposition. 35 (8): 1387–1392. doi:10.1124/dmd.107.015768. PMID17494642. S2CID25558546.
^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 Practice. 50 (3): 203. PMID11252203.
^Prisco V, Iannaccone T, Di Grezia G (1 April 2017). "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. S2CID148816505.
^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 Pharmacology. 54 (9–10): 761–766. doi:10.1007/s002280050548. PMID9923581. S2CID21939719.
^ abcRoth 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.
^Nelson DR, Thomas DR (May 1989). "[3H]-BRL 43694 (Granisetron), a specific ligand for 5-HT3 binding sites in rat brain cortical membranes". Biochemical Pharmacology. 38 (10): 1693–1695. doi:10.1016/0006-2952(89)90319-5. PMID2543418.
^ abBorsini 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 Pharmacology. 352 (3): 276–282. doi:10.1007/bf00168557. PMID8584042. S2CID19340842.
^Plassat JL, Amlaiky N, Hen R (August 1993). "Molecular cloning of a mammalian serotonin receptor that activates adenylate cyclase". Molecular Pharmacology. 44 (2): 229–236. PMID8394987.
^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". Neuron. 11 (3): 449–458. doi:10.1016/0896-6273(93)90149-l. PMID8398139. S2CID28729004.
^Perry CK, Casey AB, Felsing DE, Vemula R, Zaka M, Herrington NB, et al. (February 2020). "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. doi:10.1016/j.bmc.2019.115262. PMID31882369. S2CID209498915.
^ abBlier 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". Neuropharmacology. 30 (7): 691–701. doi:10.1016/0028-3908(91)90176-c. PMID1681447. S2CID44297577.
^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 Therapeutics. 303 (3): 1130–1137. doi:10.1124/jpet.102.036798. PMID12438536. S2CID14139919.
^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 Pharmacology. 46 (11): 1308–1312. doi:10.1177/0091270006292250. PMID17050795. S2CID25050964.
^Jajoo HK, Mayol RF, LaBudde JA, Blair IA (1989). "Metabolism of the antianxiety drug buspirone in human subjects". Drug Metabolism and Disposition. 17 (6): 634–640. PMID2575499.
^Yevich, J. P., Temple, D. L., New, J. S., Taylor, D. P., Riblet, L. A. (February 1983). "Buspirone analogs. 1. Structure-activity relationships in a series of N-aryl- and heteroarylpiperazine derivatives". Journal of Medicinal Chemistry. 26 (2): 194–203. doi:10.1021/jm00356a014. PMID6131130. S2CID28619843.
^Cybulski, Jacek; Chilmonczyk, Zdzislaw; Szelejewski, Wieslaw; Wojtasiewicz, Krystyna; Wróbel, Jerzy T. (1992). "An Efficient Synthesis of Buspirone and its Analogues.". Archiv der Pharmazie. 325 (5): 313–315. doi:10.1002/ardp.19923250513.
^L. Kuo, David (1993). "Pd(0)-catalysed Synthesis of Buspirone and Gepirone". HETEROCYCLES. 36 (7): 1463. doi:10.3987/COM-93-6357.