View source for Azapirone

{{Short description|Drug class of psycotropic drugs}}
{{cs1 config|name-list-style=vanc}}
{{Use mdy dates|date=May 2023}}
[[File:Buspirone.svg|thumb|right|250px|[[Buspirone]], the prototypical azapirone anxiolytic, which contains [[azaspirodecanedione]] and [[pyrimidinylpiperazine]] bound via a [[butyl]] chain.]]

'''Azapirones''' are a class of [[drug]]s used as [[anxiolytic]]s, [[antidepressant]]s, and [[antipsychotic]]s.<ref name="pmid1973936">{{cite journal | author = Eison AS | title = Azapirones: history of development | journal = Journal of Clinical Psychopharmacology | volume = 10 | issue = 3 Suppl | pages = 2S–5S |date=June 1990 | pmid = 1973936 | doi = 10.1097/00004714-199006001-00002| s2cid = 40578767 }}</ref><ref name="pmid8638511">{{cite journal | author = Cadieux RJ | title = Azapirones: an alternative to benzodiazepines for anxiety | journal = American Family Physician | volume = 53 | issue = 7 | pages = 2349–53 |date=May 1996 | pmid = 8638511 }}</ref><ref name="pmid16856115">{{cite journal | vauthors=Chessick CA, Allen MH, Thase M, Batista Miralha da Cunha AB, Kapczinski FF, de Lima MS, dos Santos Souza JJ | title = Azapirones for generalized anxiety disorder | journal = Cochrane Database of Systematic Reviews | volume = 3 | issue = 3| pages = CD006115 | year = 2006 | pmid = 16856115 | editor1-last = Chessick | editor1-first = Cheryl A |  doi = 10.1002/14651858.CD006115| pmc = 8915394 |display-authors=etal}}</ref><ref name="pmid2567039">{{cite journal |vauthors=Feighner JP, Boyer WF | title = Serotonin-1A anxiolytics: an overview | journal = Psychopathology | volume = 22 Suppl 1 | issue = 1| pages = 21–6 | year = 1989 | pmid = 2567039 | doi = 10.1159/000284623}}</ref> They are commonly used as [[Augmentation (psychiatry)|add-on]]s to other [[antidepressant]]s, such as [[selective serotonin reuptake inhibitor]]s (SSRIs).<ref>{{Cite book|chapter = Pharmacological treatment of social anxiety disorder|doi = 10.1159/000351960|pmid = 25225024 |volume=29 |year=2013 |pages=144–53 |vauthors=Masdrakis VG, Turic D, Baldwin DS|isbn = 978-3-318-02463-0|title = Anxiety Disorders|series = Modern Trends in Pharmacopsychiatry}}</ref><ref name="pmid8827420">{{cite journal |vauthors=Van Ameringen M, Mancini C, Wilson C | title = Buspirone augmentation of selective serotonin reuptake inhibitors (SSRIs) in social phobia | journal = Journal of Affective Disorders | volume = 39 | issue = 2 | pages = 115–21 |date=July 1996 | pmid = 8827420 | doi = 10.1016/0165-0327(96)00030-4}}</ref><ref name="pmid9180827">{{cite journal |vauthors=Bouwer C, Stein DJ | title = Buspirone is an effective augmenting agent of serotonin selective re-uptake inhibitors in severe treatment-refractory depression | journal = South African Medical Journal | volume = 87 | issue = 4 Suppl | pages = 534–7, 540 |date=April 1997 | pmid = 9180827 }}</ref><ref name="pmid9864079">{{cite journal |vauthors=Dimitriou EC, Dimitriou CE | title = Buspirone augmentation of antidepressant therapy | journal = Journal of Clinical Psychopharmacology | volume = 18 | issue = 6 | pages = 465–9 |date=December 1998 | pmid = 9864079 | doi = 10.1097/00004714-199812000-00009}}</ref><ref name="pmid11465522">{{cite journal |vauthors=Appelberg BG, Syvälahti EK, Koskinen TE, Mehtonen OP, Muhonen TT, Naukkarinen HH | title = Patients with severe depression may benefit from buspirone augmentation of selective serotonin reuptake inhibitors: results from a placebo-controlled, randomized, double-blind, placebo wash-in study | journal = The Journal of Clinical Psychiatry | volume = 62 | issue = 6 | pages = 448–52 |date=June 2001 | pmid = 11465522 | doi = 10.4088/JCP.v62n0608}}</ref><ref name="pmid12667165">{{cite journal |vauthors=Yamada K, Yagi G, Kanba S | title = Clinical efficacy of tandospirone augmentation in patients with major depressive disorder: a randomized controlled trial | journal = Psychiatry and Clinical Neurosciences | volume = 57 | issue = 2 | pages = 183–7 |date=April 2003 | pmid = 12667165 | doi = 10.1046/j.1440-1819.2003.01099.x| doi-access = free }}</ref>

== List of azapirones ==

The azapirones include the following agents:<ref name="who">{{cite web | url = http://apps.who.int/medicinedocs/en/d/Js4895e/6.html | archive-url = https://web.archive.org/web/20170731013011/http://apps.who.int:80/medicinedocs/en/d/Js4895e/6.html | url-status = dead | archive-date = 2017-07-31 | title = The Use of Common Stems in the Selection of International Nonproprietary Names (INN) for Pharmaceutical Substances: Alphabetical list of stems together with corresponding INNs }}</ref>

{{div col|colwidth=30em}}
; Anxiolytics
* [[Alnespirone]] (S-20,499)
* [[Binospirone]] (MDL-73,005)
* [[BMY-7,378]] (CAS number: {{CAS|21102-95-4}})
* [[Buspirone]] (Buspar)
* [[Enilospirone]] (CERM-3,726)
* [[Eptapirone]] (F-11,440)
* [[Gepirone]] (Exxua)
* [[Ipsapirone]] (TVX-Q-7,821)
* MJ-7378<ref>{{PubChem|10319570}}</ref> (CAS number: {{CAS|21103-03-7}})
* [[Revospirone]] (BAY-VQ-7,813)
* [[Tandospirone]] (Sediel)
* [[Zalospirone]] (WY-47,846)
; Antipsychotics
* [[Perospirone]] (Lullan)
* [[Tiospirone]] (BMY-13,859)
* [[Umespirone]] (KC-9,172)
; others
*SNAP-8719<ref>{{PubChem|9845181}}</ref> (CAS number: {{CAS|255893-38-0}})
*[https://pubchem.ncbi.nlm.nih.gov/compound/14086451 CID:14086451]
{{div col end}}

==Medical uses==
Azapirones have shown benefit in general anxiety<ref>{{Cite journal|title = Azapirones for generalized anxiety disorder.|journal = Reviews|doi = 10.1002/14651858.CD006115|pmid = 16856115 |issue=3 |year=2006 |pages=CD006115 |vauthors=Chessick CA, Allen MH, Thase M | volume=2015 | pmc=8915394 |display-authors=etal}}</ref> and augmenting SSRIs in social anxiety<ref>{{Cite book|chapter = Pharmacological treatment of social anxiety disorder|date = Sep 20, 2013 |doi = 10.1159/000351960|pmid = 25225024 |volume=29 |pages=144–53 |vauthors=Masdrakis VG, Turic D, Baldwin DS |isbn = 978-3-318-02463-0|title = Anxiety Disorders|series = Modern Trends in Pharmacopsychiatry}}</ref> and depression.<ref>{{Cite journal|title = Serotonergic drugs for depression and beyond|date = May 1, 2013|last1 = Stahl |first1=SM |last2 =Lee-Zimmerman |first2=C |journal = Curr Drug Targets|pmid = 23531115 |volume=14 |issue=5 |pages=578–85 |doi=10.2174/1389450111314050007}}</ref> Evidence is not clear for [[panic disorder]]<ref>{{cite journal|last1=Imai|first1=H|last2=Tajika|first2=A|last3=Chen|first3=P|last4=Pompoli|first4=A|last5=Guaiana|first5=G|last6=Castellazzi|first6=M|last7=Bighelli|first7=I|last8=Girlanda|first8=F|last9=Barbui|first9=C|last10=Koesters|first10=M|last11=Cipriani|first11=A|last12=Furukawa|first12=TA|title=Azapirones versus placebo for panic disorder in adults|journal=The Cochrane Database of Systematic Reviews|date=Sep 30, 2014|volume=2014|issue=9|pages=CD010828|pmid=25268297|doi=10.1002/14651858.CD010828.pub2|pmc=10590499}}</ref> and [[functional gastrointestinal disorder]]s.<ref>{{Cite journal|title = Effects on gastrointestinal functions and symptoms of serotonergic psychoactive agents used in functional gastrointestinal diseases|date = Feb 2013|journal = J Gastroenterol|doi = 10.1007/s00535-012-0726-5|pmid = 23254779 |volume=48 |issue=2 |pages=177–81 |pmc=3698430 |vauthors=Grover M, Camilleri M}}</ref>

[[Tandospirone]] has also been used to augment antipsychotics in [[Japan]] as it improves [[Schizophrenia#Positive and negative|cognitive]] and [[Schizophrenia#Positive and negative|negative symptom]]s of [[schizophrenia]].<ref name="pmid11579010">{{cite journal |vauthors=Sumiyoshi T, Matsui M, Nohara S | title = Enhancement of cognitive performance in schizophrenia by addition of tandospirone to neuroleptic treatment | journal = The American Journal of Psychiatry | volume = 158 | issue = 10 | pages = 1722–5 |date=October 2001 | pmid = 11579010 | doi = 10.1176/appi.ajp.158.10.1722|display-authors=etal}}</ref> [[Buspirone]] is being investigated for this purpose as well.<ref name="pmid17628435">{{cite journal |vauthors=Sumiyoshi T, Park S, Jayathilake K, Roy A, Ertugrul A, Meltzer HY | title = Effect of buspirone, a serotonin1A partial agonist, on cognitive function in schizophrenia: a randomized, double-blind, placebo-controlled study | journal = Schizophrenia Research | volume = 95 | issue = 1–3 | pages = 158–68 |date=September 2007 | pmid = 17628435 | doi = 10.1016/j.schres.2007.06.008 | s2cid = 36027848 }}</ref><ref name="pmid19637398">{{cite journal |vauthors=Piskulić D, Olver JS, Maruff P, Norman TR | title = Treatment of cognitive dysfunction in chronic schizophrenia by augmentation of atypical antipsychotics with buspirone, a partial 5-HT(1A) receptor agonist | journal = Human Psychopharmacology | volume = 24 | issue = 6 | pages = 437–46 |date=August 2009 | pmid = 19637398 |  doi = 10.1002/hup.1046| s2cid = 21289248 | doi-access = free }}</ref>

== Side effects ==
Side effects of azapirones may include [[dizziness]], [[headache]]s, [[Psychomotor agitation|restlessness]], [[nausea]], and [[diarrhea]].<ref name="pmid2567039"/><ref name="pmid2870641">{{cite journal |vauthors=Newton RE, Marunycz JD, Alderdice MT, Napoliello MJ | title = Review of the side-effect profile of buspirone | journal = The American Journal of Medicine | volume = 80 | issue = 3B | pages = 17–21 |date=March 1986 | pmid = 2870641 | doi = 10.1016/0002-9343(86)90327-X}}</ref>

Azapirones have more tolerable adverse effects than many other available anxiolytics, such as [[benzodiazepine]]s or SSRIs. Unlike benzodiazepines, azapirones lack [[abuse potential]] and are not [[Substance use disorder|addictive]], do not cause [[cognitive deficit|cognitive/memory impairment]] or [[sedation]], and do not appear to induce appreciable [[Drug tolerance|tolerance]] or [[physical dependence]]. However, azapirones are considered less effective with slow onset in controlling symptoms.<ref>{{Cite journal|title = Management of Generalized Anxiety Disorder in Primary Care: Identifying the Challenges and Unmet Needs|date = 2010|journal = Prim Care Companion J Clin Psychiatry|doi = 10.4088/PCC.09r00772blu|pmid = 20694114 |volume=12 |issue=2 |pmc=2911006 |vauthors=Davidson JR, Feltner DE, Dugar A}}</ref>

== Chemistry ==

[[Buspirone]] was originally classified as an [[azaspirodecanedione]], shortened to azapirone or azaspirone due to the fact that its [[chemical structure]] contained this [[functional group|moiety]], and other drugs with similar structures were labeled as such as well. However, despite all being called azapirones, not all of them actually contain the azapirodecanedione component, and most in fact do not or contain a variation of it. Additionally, many azapirones are also [[pyrimidinylpiperazine]]s, though again this does not apply to them all.

Drugs classed as azapirones can be identified by their -''spirone'' or -''pirone'' suffix.<ref name="urlThe use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances">{{cite web | url = http://libdoc.who.int/hq/2004/who_edm_qsm_2004.5.pdf | title = The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances | year = 2004 | access-date = 1 April 2010 | archive-url = https://web.archive.org/web/20110722013129/http://libdoc.who.int/hq/2004/who_edm_qsm_2004.5.pdf | archive-date = 2011-07-22 | url-status = dead }}</ref>

== Pharmacology ==

=== Pharmacodynamics ===

On a [[pharmacological]] level, azapirones varyingly possess activity at the following [[receptor (biochemistry)|receptor]]s:<ref name="pmid1974152">{{cite journal |pmid=1974152 |year=1990 |author1=Hamik |last2=Oksenberg |first2=D |last3=Fischette |first3=C |last4=Peroutka |first4=SJ |title=Analysis of tandospirone (SM-3997) interactions with neurotransmitter receptor binding sites |volume=28 |issue=2 |pages=99–109 |journal=Biological Psychiatry |doi=10.1016/0006-3223(90)90627-E |s2cid=25608914 |doi-access=free }}</ref><ref name="pmid1685786">{{cite journal |vauthors=Barnes NM, Costall B, Domeney AM | title = The effects of umespirone as a potential anxiolytic and antipsychotic agent | journal = Pharmacology Biochemistry and Behavior | volume = 40 | issue = 1 | pages = 89–96 |date=September 1991 | pmid = 1685786 | doi = 10.1016/0091-3057(91)90326-W| s2cid = 9762359 |display-authors=etal}}</ref><ref name="pmid1361441">{{cite journal |vauthors=Ahlenius S, Wijkström A | title = Mixed agonist-antagonist properties of umespirone at neostriatal dopamine receptors in relation to its behavioral effects in the rat | journal = European Journal of Pharmacology | volume = 222 | issue = 1 | pages = 69–74 |date=November 1992 | pmid = 1361441 | doi = 10.1016/0014-2999(92)90464-F}}</ref><ref name="pmid7766287">{{cite journal |vauthors=Sumiyoshi T, Suzuki K, Sakamoto H | title = Atypicality of several antipsychotics on the basis of in vivo dopamine-D2 and serotonin-5HT2 receptor occupancy | journal = Neuropsychopharmacology | volume = 12 | issue = 1 | pages = 57–64 |date=February 1995 | pmid = 7766287 |  doi = 10.1016/0893-133X(94)00064-7|display-authors=etal}}</ref><ref name="pmid11561089">{{cite journal |vauthors=Weiner DM, Burstein ES, Nash N | title = 5-hydroxytryptamine2A receptor inverse agonists as antipsychotics | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 299 | issue = 1 | pages = 268–76 |date=October 2001 | pmid = 11561089 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11561089|display-authors=etal}}</ref><ref name="pmid1975278">{{cite journal |vauthors=Hirose A, Kato T, Ohno Y | title = Pharmacological actions of SM-9018, a new neuroleptic drug with both potent 5-hydroxytryptamine2 and dopamine2 antagonistic actions | journal = Japanese Journal of Pharmacology | volume = 53 | issue = 3 | pages = 321–9 |date=July 1990 | pmid = 1975278 | doi = 10.1254/jjp.53.321|display-authors=etal| doi-access = free }}</ref><ref name="pmid1982326">{{cite journal |vauthors=Kato T, Hirose A, Ohno Y, Shimizu H, Tanaka H, Nakamura M | title = Binding profile of SM-9018, a novel antipsychotic candidate | journal = Japanese Journal of Pharmacology | volume = 54 | issue = 4 | pages = 478–81 |date=December 1990 | pmid = 1982326 | doi = 10.1254/jjp.54.478| doi-access = free }}</ref><ref name="pmid17439416">{{cite journal | vauthors = Odagaki Y, Toyoshima R | title = 5-HT1A receptor agonist properties of antipsychotics determined by [35S]GTPgammaS binding in rat hippocampal membranes | journal = Clinical and Experimental Pharmacology & Physiology | volume = 34 | issue = 5–6 | pages = 462–6 | year = 2007 | pmid = 17439416 | doi = 10.1111/j.1440-1681.2007.04595.x | s2cid = 22450517 }}</ref>

* [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]] (as [[partial agonist|partial]] or [[full agonist]]s)
* [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]] (as [[inverse agonist]]s)
* [[D2 receptor|D<sub>2</sub> receptor]] (as [[receptor antagonist|antagonist]]s or partial agonists)
* [[α1-adrenergic receptor|α<sub>1</sub>-adrenergic receptor]] (as antagonists)
* [[α2-adrenergic receptor|α<sub>2</sub>-adrenergic receptor]] (as antagonists)

Actions at [[D4 receptor|D<sub>4</sub>]], [[5-HT2C receptor|5-HT<sub>2C</sub>]], [[5-HT7 receptor|5-HT<sub>7</sub>]], and [[sigma receptor]]s have also been shown for some azapirones.<ref name="pmid8524985">{{cite journal|author1-link=Bryan Roth |vauthors=Roth BL, Tandra S, Burgess LH, Sibley DR, Meltzer HY | title = D4 dopamine receptor binding affinity does not distinguish between typical and atypical antipsychotic drugs | journal = Psychopharmacology | volume = 120 | issue = 3 | pages = 365–8 |date=August 1995 | pmid = 8524985 | doi = 10.1007/BF02311185|s2cid=13549491 }}</ref><ref name="pmid10991983">{{cite journal |vauthors=Herrick-Davis K, Grinde E, Teitler M | title = Inverse agonist activity of atypical antipsychotic drugs at human 5-hydroxytryptamine2C receptors | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 295 | issue = 1 | pages = 226–32 |date=October 2000 | pmid = 10991983 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10991983}}</ref><ref name="pmid17786406">{{cite journal |vauthors=Rauly-Lestienne I, Boutet-Robinet E, Ailhaud MC, Newman-Tancredi A, Cussac D | title = Differential profile of typical, atypical and third generation antipsychotics at human 5-HT7a receptors coupled to adenylyl cyclase: detection of agonist and inverse agonist properties | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 376 | issue = 1–2 | pages = 93–105 |date=October 2007 | pmid = 17786406 | doi = 10.1007/s00210-007-0182-6 | s2cid = 29337002 }}</ref><ref name="pmid1970425">{{cite journal |vauthors=Itzhak Y, Ruhland M, Krähling H | title = Binding of umespirone to the sigma receptor: evidence for multiple affinity states | journal = Neuropharmacology | volume = 29 | issue = 2 | pages = 181–4 |date=February 1990 | pmid = 1970425 | doi = 10.1016/0028-3908(90)90058-Y| s2cid = 54326248 | doi-access = free }}</ref>

While some of the listed properties such as 5-HT<sub>2A</sub> and D<sub>2</sub> blockade may be useful in certain indications such as in the treatment of [[schizophrenia]] (as with perospirone and tiospirone), all of them except 5-HT<sub>1A</sub> agonism are generally undesirable in anxiolytics and only contribute to [[side effect]]s. As a result, further development has commenced to bring more [[binding selectivity|selective]] of anxiolytic agents to the market. An example of this initiative is gepirone, which was recently approved after completing [[clinical trial]]s in the [[United States]] for the treatment of [[major depression]] and [[generalized anxiety disorder]]. Another example is tandospirone which has been licensed in Japan for the treatment of anxiety and as an augmentation to antidepressants for depression.

5-HT<sub>1A</sub> receptor partial agonists have demonstrated efficacy against depression in [[animal testing on rodents|rodent studies]] and human clinical trials.<ref name="pmid2883013">{{cite journal |vauthors=Kennett GA, Dourish CT, Curzon G | title = Antidepressant-like action of 5-HT1A agonists and conventional antidepressants in an animal model of depression | journal = European Journal of Pharmacology | volume = 134 | issue = 3 | pages = 265–74 |date=February 1987 | pmid = 2883013 | doi = 10.1016/0014-2999(87)90357-8}}</ref><ref name="pmid12559651">{{cite journal |vauthors=Blier P, Ward NM | title = Is there a role for 5-HT1A agonists in the treatment of depression? | journal = Biological Psychiatry | volume = 53 | issue = 3 | pages = 193–203 |date=February 2003 | pmid = 12559651 | doi = 10.1016/S0006-3223(02)01643-8| s2cid = 23792607 }}</ref><ref name="pmid2198303">{{cite journal |vauthors=Robinson DS, Rickels K, Feighner J | title = Clinical effects of the 5-HT1A partial agonists in depression: a composite analysis of buspirone in the treatment of depression | journal = Journal of Clinical Psychopharmacology | volume = 10 | issue = 3 Suppl | pages = 67S–76S |date=June 1990 | pmid = 2198303 | doi = 10.1097/00004714-199006001-00013| s2cid = 7849957 |display-authors=etal}}</ref><ref name="pmid18373383">{{cite journal |vauthors=Bielski RJ, Cunningham L, Horrigan JP, Londborg PD, Smith WT, Weiss K | title = Gepirone extended-release in the treatment of adult outpatients with major depressive disorder: a double-blind, randomized, placebo-controlled, parallel-group study | journal = The Journal of Clinical Psychiatry | volume = 69 | issue = 4 | pages = 571–7 |date=April 2008 | pmid = 18373383 | doi = 10.4088/jcp.v69n0408| s2cid = 39524249 }}</ref> Unfortunately, however, their efficacy is limited and they are only relatively mild antidepressants. Instead of being used as monotherapy treatments, they are more commonly employed as augmentations to serotonergic antidepressants like the SSRIs.<ref name="pmid8827420"/><ref name="pmid9180827"/><ref name="pmid9864079"/><ref name="pmid11465522"/><ref name="pmid12667165"/> It has been proposed that high [[intrinsic activity]] at 5-HT<sub>1A</sub> postsynaptic receptors is necessary for maximal therapeutic benefits to come to prominence, and as a result, investigation has commenced in azapirones which act as 5-HT<sub>1A</sub> receptor full agonists such as alnespirone and eptapirone.<ref name="pmid9765347">{{cite journal |vauthors=Koek W, Patoiseau JF, Assié MB | title = F 11440, a potent, selective, high efficacy 5-HT1A receptor agonist with marked anxiolytic and antidepressant potential | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 287 | issue = 1 | pages = 266–83 |date=October 1998 | pmid = 9765347 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9765347|display-authors=etal}}</ref><ref name="pmid11408031">{{cite journal |vauthors=Koek W, Vacher B, Cosi C | title = 5-HT1A receptor activation and antidepressant-like effects: F 13714 has high efficacy and marked antidepressant potential | journal = European Journal of Pharmacology | volume = 420 | issue = 2–3 | pages = 103–12 |date=May 2001 | pmid = 11408031 | doi = 10.1016/S0014-2999(01)01011-1|display-authors=etal}}</ref><ref name="pmid12398907">{{cite journal |vauthors=Prinssen EP, Colpaert FC, Koek W | title = 5-HT1A receptor activation and anti-cataleptic effects: high-efficacy agonists maximally inhibit haloperidol-induced catalepsy | journal = European Journal of Pharmacology | volume = 453 | issue = 2–3 | pages = 217–21 |date=October 2002 | pmid = 12398907 | doi = 10.1016/S0014-2999(02)02430-5}}</ref><ref name="pmid17803293">{{cite journal |vauthors=Maurel JL, Autin JM, Funes P, Newman-Tancredi A, Colpaert F, Vacher B | title = High-efficacy 5-HT1A agonists for antidepressant treatment: a renewed opportunity | journal = Journal of Medicinal Chemistry | volume = 50 | issue = 20 | pages = 5024–33 |date=October 2007 | pmid = 17803293 |  doi = 10.1021/jm070714l}}</ref> Indeed, in [[Preclinical development|preclinical studies]], eptapirone produces robust antidepressant effects which surpass those of even high doses of [[imipramine]] and [[paroxetine]].<ref name="pmid9765347"/><ref name="pmid11408031"/><ref name="pmid12398907"/><ref name="pmid17803293"/>

====Comparison of binding profiles====
{| class="wikitable"
|+ Affinities of Azapirones for Neurotransmitter Binding Sites (K<sub>i</sub>, nM)<ref name="pmid1974152" />
|-
! [[Binding site]] || [[Buspirone]] || [[Gepirone]] || [[Ipsapirone]] || [[Tandospirone]]
|-
| [[5-HT1A receptor|5-HT<sub>1A</sub>]] || 20 ± 3 || 70 ± 10 || 7.9 ± 2 || 27 ± 5
|-
| [[5-HT1B receptor|5-HT<sub>1B</sub>]] || > 100,000 || > 100,000 || > 100,000 || > 100,000
|-
| [[5-HT1D receptor|5-HT<sub>1D</sub>]] || > 100,000 || > 100,000 || 33,000 ± 8,000 || > 100,000
|-
| [[5-HT2A receptor|5-HT<sub>2A</sub>]] || 1,300 ± 400 || 3,000 ± 50 || 6,400 ± 4,000 || 1,300 ± 200
|-
| [[5-HT2C receptor|5-HT<sub>2C</sub>]] || 1,100 ± 200 || 5,000 ± 700 || 5,000 ± 1,000 || 2,600 ± 60
|-
| {{abbrlink|SERT|Serotonin transporter}} || – || – || – || > 100,000
|-
| [[D1 receptor|D<sub>1</sub>]] || 33,000 ± 1,000 || > 100,000 || 15,000 ± 2,000 || 41,000 ± 10,000
|-
| [[D2 receptor|D<sub>2</sub>]] || 240 ± 50 || 2,200 ± 200 || 1,900 ± 200 || 1,700 ± 300
|-
| [[Alpha-1 adrenergic receptor|α<sub>1</sub>-Adrenergic]] || 1,000 ± 400 || 2,300 ± 300 || 40 ± 7 || 1,600 ± 80
|-
| [[Alpha-2 adrenergic receptor|α<sub>2</sub>-Adrenergic]] || 6,000 ± 700 || 1,600 ± 200 || 1,900 ± 500 || 1,900 ± 400
|-
| [[Beta-adrenergic receptor|β-Adrenergic]] || 8,800 ± 1,000 || > 100,000 || > 100,000 || > 100,000
|-
| {{abbrlink|mACh|Muscarinic acetylcholine receptor}} || 38,000 ± 5,000 || > 100,000 || 49,000 ± 5,000 || > 100,000
|-
| [[GABAA receptor#Benzodiazepine site|GABA<sub>A</sub>/{{abbr|BDZ|Benzodiazepine site}}]] || > 100,000 || > 100,000 || > 100,000 || > 100,000
|}

=== Pharmacokinetics ===

Azapirones are poorly but nonetheless appreciably [[absorption (pharmacokinetics)|absorbed]] and have a rapid [[onset of action]], but have only very short [[half-life|half-live]]s ranging from 1–3 hours. As a result, they must be administered 2&ndash;3 times a day. The only exception to this rule is umespirone, which has a very long duration with a single dose lasting as long as 23 hours.<ref name="pmid7957544">{{cite journal |vauthors=Holland RL, Wesnes K, Dietrich B | title = Single dose human pharmacology of umespirone | journal = European Journal of Clinical Pharmacology | volume = 46 | issue = 5 | pages = 461–8 | year = 1994 | pmid = 7957544 | doi = 10.1007/bf00191912| s2cid = 12117650 }}</ref> Unfortunately, umespirone has not been commercialized. Although never commercially produced, Bristol-Myers Squibb applied for a patent on October 28, 1993, and received the patent on July 11, 1995, for an extended release formulation of buspirone.<ref>{{ cite patent | country = US | number = 5431922 | status = patent | title = Method for administration of buspirone | gdate = 1995-07-11 | fdate =  1993-10-23 | inventor = Nicklasson AGM | assign1 = Bristol-Myers Squibb Company url=https://patents.google.com/patent/US5431922 }}</ref> An [[Time Release Technology (medicine)|extended release]] formulation of gepirone is currently under development and if approved, should help to improve this issue.

[[Metabolism]] of azapirones occurs in the [[liver]] and they are [[excretion|excreted]] in [[urine]] and [[feces]]. A common [[metabolite]] of several azapirones including [[buspirone]], [[gepirone]], [[ipsapirone]], [[revospirone]], and [[tandospirone]] is [[1-(2-pyrimidinyl)piperazine]] (1-PP).<ref name="pmid8750726">{{cite journal |vauthors=Manahan-Vaughan D, Anwyl R, Rowan MJ | title = The azapirone metabolite 1-(2-pyrimidinyl)piperazine depresses excitatory synaptic transmission in the hippocampus of the alert rat via 5-HT1A receptors | journal = European Journal of Pharmacology | volume = 294 | issue = 2–3 | pages = 617–24 |date=December 1995 | pmid = 8750726 | doi = 10.1016/0014-2999(95)00605-2}}</ref><ref name="pmid1681447">{{cite journal |vauthors=Blier P, Curet O, Chaput Y, de Montigny C | title = 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 | journal = Neuropharmacology | volume = 30 | issue = 7 | pages = 691–701 |date=July 1991 | pmid = 1681447 | doi = 10.1016/0028-3908(91)90176-C| s2cid = 44297577 }}</ref><ref name="pmid2149168">{{cite journal |vauthors=Löscher W, Witte U, Fredow G, Traber J, Glaser T | title = The behavioural responses to 8-OH-DPAT, ipsapirone and the novel 5-HT1A receptor agonist Bay Vq 7813 in the pig | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 342 | issue = 3 | pages = 271–7 |date=September 1990 | pmid = 2149168 | doi = 10.1007/bf00169437| s2cid = 24769939 }}</ref> 1-PP possesses 5-HT<sub>1A</sub> partial agonist and α<sub>2</sub>-adrenergic antagonist actions and likely contributes overall mostly to side effects.<ref name="pmid8750726"/><ref name="pmid1681447"/><ref name="pmid12438536">{{cite journal |vauthors=Zuideveld KP, Rusiç-Pavletiç J, Maas HJ, Peletier LA, Van der Graaf PH, Danhof M | title = Pharmacokinetic-pharmacodynamic modeling of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine in rats | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 303 | issue = 3 | pages = 1130–7 |date=December 2002 | pmid = 12438536 | doi = 10.1124/jpet.102.036798 | s2cid = 14139919 }}</ref>

== References ==
{{Reflist|2}}

{{Anxiolytics}}
{{Antidepressants}}
{{Antipsychotics}}
{{Adrenergics}}
{{Dopaminergics}}
{{Serotonergics}}
{{Sigmaergics}}
{{Piperazines}}

[[Category:Azapirones| ]]