Editing Azapirone (section)

=== 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
|}