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Azapirone

January 01, 1970

Azapirones are a class of drugs used as anxiolytics, antidepressants, and antipsychotics.[1][2][3][4] They are commonly used as add-ons to other antidepressants, such as selective serotonin reuptake inhibitors (SSRIs).[5][6][7][8][9][10]

Buspirone, the prototypical azapirone anxiolytic, which contains azaspirodecanedione and pyrimidinylpiperazine bound via a butyl chain.

List of azapirones edit

The azapirones include the following agents:[11]

Anxiolytics
Antipsychotics
others
  • SNAP-8719[13] (CAS number: 255893-38-0 )

Medical uses edit

Azapirones have shown benefit in general anxiety[14] and augmenting SSRIs in social anxiety[15] and depression.[16] Evidence is not clear for panic disorder[17] and functional gastrointestinal disorders.[18]

Tandospirone has also been used to augment antipsychotics in Japan as it improves cognitive and negative symptoms of schizophrenia.[19] Buspirone is being investigated for this purpose as well.[20][21]

Side effects edit

Side effects of azapirones may include dizziness, headaches, restlessness, nausea, and diarrhea.[4][22]

Azapirones have more tolerable adverse effects than many other available anxiolytics, such as benzodiazepines or SSRIs. Unlike benzodiazepines, azapirones lack abuse potential and are not addictive, do not cause cognitive/memory impairment or sedation, and do not appear to induce appreciable tolerance or physical dependence. However, azapirones are considered less effective with slow onset in controlling symptoms.[23]

Chemistry edit

Buspirone was originally classified as an azaspirodecanedione, shortened to azapirone or azaspirone due to the fact that its chemical structure contained this 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 pyrimidinylpiperazines, though again this does not apply to them all.

Drugs classed as azapirones can be identified by their -spirone or -pirone suffix.[24]

Pharmacology edit

Pharmacodynamics edit

On a pharmacological level, azapirones varyingly possess activity at the following receptors:[25][26][27][28][29][30][31][32]

Actions at D4, 5-HT2C, 5-HT7, and sigma receptors have also been shown for some azapirones.[33][34][35][36]

While some of the listed properties such as 5-HT2A and D2 blockade may be useful in certain indications such as in the treatment of schizophrenia (as with perospirone and tiospirone), all of them except 5-HT1A agonism are generally undesirable in anxiolytics and only contribute to side effects. As a result, further development has commenced to bring more selective of anxiolytic agents to the market. An example of this initiative is gepirone, which was recently approved after completing clinical trials 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-HT1A receptor partial agonists have demonstrated efficacy against depression in rodent studies and human clinical trials.[37][38][39][40] 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.[6][7][8][9][10] It has been proposed that high intrinsic activity at 5-HT1A 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-HT1A receptor full agonists such as alnespirone and eptapirone.[41][42][43][44] Indeed, in preclinical studies, eptapirone produces robust antidepressant effects which surpass those of even high doses of imipramine and paroxetine.[41][42][43][44]

Comparison of binding profiles edit

Affinities of Azapirones for Neurotransmitter Binding Sites (Ki, nM)[25]
Binding site Buspirone Gepirone Ipsapirone Tandospirone
5-HT1A 20 ± 3 70 ± 10 7.9 ± 2 27 ± 5
5-HT1B > 100,000 > 100,000 > 100,000 > 100,000
5-HT1D > 100,000 > 100,000 33,000 ± 8,000 > 100,000
5-HT2A 1,300 ± 400 3,000 ± 50 6,400 ± 4,000 1,300 ± 200
5-HT2C 1,100 ± 200 5,000 ± 700 5,000 ± 1,000 2,600 ± 60
SERTTooltip Serotonin transporter – – – > 100,000
D1 33,000 ± 1,000 > 100,000 15,000 ± 2,000 41,000 ± 10,000
D2 240 ± 50 2,200 ± 200 1,900 ± 200 1,700 ± 300
α1-Adrenergic 1,000 ± 400 2,300 ± 300 40 ± 7 1,600 ± 80
α2-Adrenergic 6,000 ± 700 1,600 ± 200 1,900 ± 500 1,900 ± 400
β-Adrenergic 8,800 ± 1,000 > 100,000 > 100,000 > 100,000
mAChTooltip Muscarinic acetylcholine receptor 38,000 ± 5,000 > 100,000 49,000 ± 5,000 > 100,000
GABAA/BDZ > 100,000 > 100,000 > 100,000 > 100,000

Pharmacokinetics edit

Azapirones are poorly but nonetheless appreciably absorbed and have a rapid onset of action, but have only very short half-lives ranging from 1–3 hours. As a result, they must be administered 2–3 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.[45] 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.[46] An 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 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).[47][48][49] 1-PP possesses 5-HT1A partial agonist and α2-adrenergic antagonist actions and likely contributes overall mostly to side effects.[47][48][50]

References edit

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January 01, 1970
azapirone, class, drugs, used, anxiolytics, antidepressants, antipsychotics, they, commonly, used, other, antidepressants, such, selective, serotonin, reuptake, inhibitors, ssris, buspirone, prototypical, azapirone, anxiolytic, which, contains, azaspirodecaned. Azapirones are a class of drugs used as anxiolytics antidepressants and antipsychotics 1 2 3 4 They are commonly used as add ons to other antidepressants such as selective serotonin reuptake inhibitors SSRIs 5 6 7 8 9 10 Buspirone the prototypical azapirone anxiolytic which contains azaspirodecanedione and pyrimidinylpiperazine bound via a butyl chain Contents 1 List of azapirones 2 Medical uses 3 Side effects 4 Chemistry 5 Pharmacology 5 1 Pharmacodynamics 5 1 1 Comparison of binding profiles 5 2 Pharmacokinetics 6 ReferencesList of azapirones editThe azapirones include the following agents 11 Anxiolytics Alnespirone S 20 499 Binospirone MDL 73 005 BMY 7 378 CAS number 21102 95 4 Buspirone Buspar Enilospirone CERM 3 726 Eptapirone F 11 440 Gepirone Exxua Ipsapirone TVX Q 7 821 MJ 7378 12 CAS number 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 13 CAS number 255893 38 0 Medical uses editAzapirones have shown benefit in general anxiety 14 and augmenting SSRIs in social anxiety 15 and depression 16 Evidence is not clear for panic disorder 17 and functional gastrointestinal disorders 18 Tandospirone has also been used to augment antipsychotics in Japan as it improves cognitive and negative symptoms of schizophrenia 19 Buspirone is being investigated for this purpose as well 20 21 Side effects editSide effects of azapirones may include dizziness headaches restlessness nausea and diarrhea 4 22 Azapirones have more tolerable adverse effects than many other available anxiolytics such as benzodiazepines or SSRIs Unlike benzodiazepines azapirones lack abuse potential and are not addictive do not cause cognitive memory impairment or sedation and do not appear to induce appreciable tolerance or physical dependence However azapirones are considered less effective with slow onset in controlling symptoms 23 Chemistry editBuspirone was originally classified as an azaspirodecanedione shortened to azapirone or azaspirone due to the fact that its chemical structure contained this 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 pyrimidinylpiperazines though again this does not apply to them all Drugs classed as azapirones can be identified by their spirone or pirone suffix 24 Pharmacology editPharmacodynamics edit On a pharmacological level azapirones varyingly possess activity at the following receptors 25 26 27 28 29 30 31 32 5 HT1A receptor as partial or full agonists 5 HT2A receptor as inverse agonists D2 receptor as antagonists or partial agonists a1 adrenergic receptor as antagonists a2 adrenergic receptor as antagonists Actions at D4 5 HT2C 5 HT7 and sigma receptors have also been shown for some azapirones 33 34 35 36 While some of the listed properties such as 5 HT2A and D2 blockade may be useful in certain indications such as in the treatment of schizophrenia as with perospirone and tiospirone all of them except 5 HT1A agonism are generally undesirable in anxiolytics and only contribute to side effects As a result further development has commenced to bring more selective of anxiolytic agents to the market An example of this initiative is gepirone which was recently approved after completing clinical trials 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 HT1A receptor partial agonists have demonstrated efficacy against depression in rodent studies and human clinical trials 37 38 39 40 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 6 7 8 9 10 It has been proposed that high intrinsic activity at 5 HT1A 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 HT1A receptor full agonists such as alnespirone and eptapirone 41 42 43 44 Indeed in preclinical studies eptapirone produces robust antidepressant effects which surpass those of even high doses of imipramine and paroxetine 41 42 43 44 Comparison of binding profiles edit Affinities of Azapirones for Neurotransmitter Binding Sites Ki nM 25 Binding site Buspirone Gepirone Ipsapirone Tandospirone 5 HT1A 20 3 70 10 7 9 2 27 5 5 HT1B gt 100 000 gt 100 000 gt 100 000 gt 100 000 5 HT1D gt 100 000 gt 100 000 33 000 8 000 gt 100 000 5 HT2A 1 300 400 3 000 50 6 400 4 000 1 300 200 5 HT2C 1 100 200 5 000 700 5 000 1 000 2 600 60 SERTTooltip Serotonin transporter gt 100 000 D1 33 000 1 000 gt 100 000 15 000 2 000 41 000 10 000 D2 240 50 2 200 200 1 900 200 1 700 300 a1 Adrenergic 1 000 400 2 300 300 40 7 1 600 80 a2 Adrenergic 6 000 700 1 600 200 1 900 500 1 900 400 b Adrenergic 8 800 1 000 gt 100 000 gt 100 000 gt 100 000 mAChTooltip Muscarinic acetylcholine receptor 38 000 5 000 gt 100 000 49 000 5 000 gt 100 000 GABAA BDZ gt 100 000 gt 100 000 gt 100 000 gt 100 000 Pharmacokinetics edit Azapirones are poorly but nonetheless appreciably absorbed and have a rapid onset of action but have only very short half lives ranging from 1 3 hours As a result they must be administered 2 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 45 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 46 An 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 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 47 48 49 1 PP possesses 5 HT1A partial agonist and a2 adrenergic antagonist actions and likely contributes overall mostly to side effects 47 48 50 References edit Eison AS June 1990 Azapirones history of development Journal of Clinical Psychopharmacology 10 3 Suppl 2S 5S doi 10 1097 00004714 199006001 00002 PMID 1973936 S2CID 40578767 Cadieux RJ May 1996 Azapirones an alternative to benzodiazepines for anxiety American Family Physician 53 7 2349 53 PMID 8638511 Chessick CA Allen MH Thase M Batista Miralha da Cunha AB Kapczinski FF de Lima MS dos Santos Souza JJ et al 2006 Chessick CA ed Azapirones for generalized anxiety disorder Cochrane Database of Systematic Reviews 3 3 CD006115 doi 10 1002 14651858 CD006115 PMC 8915394 PMID 16856115 a b Feighner JP Boyer WF 1989 Serotonin 1A anxiolytics an overview Psychopathology 22 Suppl 1 1 21 6 doi 10 1159 000284623 PMID 2567039 Masdrakis VG Turic D Baldwin DS 2013 Pharmacological treatment of social anxiety disorder Anxiety Disorders Modern Trends in Pharmacopsychiatry Vol 29 pp 144 53 doi 10 1159 000351960 ISBN 978 3 318 02463 0 PMID 25225024 a b Van Ameringen M Mancini C Wilson C July 1996 Buspirone augmentation of selective serotonin reuptake inhibitors SSRIs in social phobia Journal of Affective Disorders 39 2 115 21 doi 10 1016 0165 0327 96 00030 4 PMID 8827420 a b Bouwer C Stein DJ April 1997 Buspirone is an effective augmenting agent of serotonin selective re uptake inhibitors in severe treatment refractory depression South African Medical Journal 87 4 Suppl 534 7 540 PMID 9180827 a b Dimitriou EC Dimitriou CE December 1998 Buspirone augmentation of antidepressant therapy Journal of Clinical Psychopharmacology 18 6 465 9 doi 10 1097 00004714 199812000 00009 PMID 9864079 a b Appelberg BG Syvalahti EK Koskinen TE Mehtonen OP Muhonen TT Naukkarinen HH June 2001 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 The Journal of Clinical Psychiatry 62 6 448 52 doi 10 4088 JCP v62n0608 PMID 11465522 a b Yamada K Yagi G Kanba S April 2003 Clinical efficacy of tandospirone augmentation in patients with major depressive disorder a randomized controlled trial Psychiatry and Clinical Neurosciences 57 2 183 7 doi 10 1046 j 1440 1819 2003 01099 x PMID 12667165 The Use of Common Stems in the Selection of International Nonproprietary Names INN for Pharmaceutical Substances Alphabetical list of stems together with corresponding INNs Archived from the original on July 31 2017 CID 10319570 from PubChem CID 9845181 from PubChem Chessick CA Allen MH Thase M et al 2006 Azapirones for generalized anxiety disorder Reviews 2015 3 CD006115 doi 10 1002 14651858 CD006115 PMC 8915394 PMID 16856115 Masdrakis VG Turic D Baldwin DS September 20 2013 Pharmacological treatment of social anxiety disorder Anxiety Disorders Modern Trends in Pharmacopsychiatry Vol 29 pp 144 53 doi 10 1159 000351960 ISBN 978 3 318 02463 0 PMID 25225024 Stahl SM Lee Zimmerman C May 1 2013 Serotonergic drugs for depression and beyond Curr Drug Targets 14 5 578 85 doi 10 2174 1389450111314050007 PMID 23531115 Imai H Tajika A Chen P Pompoli A Guaiana G Castellazzi M Bighelli I Girlanda F Barbui C Koesters M Cipriani A Furukawa TA September 30 2014 Azapirones versus placebo for panic disorder in adults The Cochrane Database of Systematic Reviews 2014 9 CD010828 doi 10 1002 14651858 CD010828 pub2 PMC 10590499 PMID 25268297 Grover M Camilleri M February 2013 Effects on gastrointestinal functions and symptoms of serotonergic psychoactive agents used in functional gastrointestinal diseases J Gastroenterol 48 2 177 81 doi 10 1007 s00535 012 0726 5 PMC 3698430 PMID 23254779 Sumiyoshi T Matsui M Nohara S et al October 2001 Enhancement of cognitive performance in schizophrenia by addition of tandospirone to neuroleptic treatment The American Journal of Psychiatry 158 10 1722 5 doi 10 1176 appi ajp 158 10 1722 PMID 11579010 Sumiyoshi T Park S Jayathilake K Roy A Ertugrul A Meltzer HY September 2007 Effect of buspirone a serotonin1A partial agonist on cognitive function in schizophrenia a randomized double blind placebo controlled study Schizophrenia Research 95 1 3 158 68 doi 10 1016 j schres 2007 06 008 PMID 17628435 S2CID 36027848 Piskulic D Olver JS Maruff P Norman TR August 2009 Treatment of cognitive dysfunction in chronic schizophrenia by augmentation of atypical antipsychotics with buspirone a partial 5 HT 1A receptor agonist Human Psychopharmacology 24 6 437 46 doi 10 1002 hup 1046 PMID 19637398 S2CID 21289248 Newton RE Marunycz JD Alderdice MT Napoliello MJ March 1986 Review of the side effect profile of buspirone The American Journal of Medicine 80 3B 17 21 doi 10 1016 0002 9343 86 90327 X PMID 2870641 Davidson JR Feltner DE Dugar A 2010 Management of Generalized Anxiety Disorder in Primary Care Identifying the Challenges and Unmet Needs Prim Care Companion J Clin Psychiatry 12 2 doi 10 4088 PCC 09r00772blu PMC 2911006 PMID 20694114 The use of stems in the selection of International Nonproprietary Names INN for pharmaceutical substances PDF 2004 Archived from the original PDF on July 22 2011 Retrieved April 1 2010 a b Hamik Oksenberg D Fischette C Peroutka SJ 1990 Analysis of tandospirone SM 3997 interactions with neurotransmitter receptor binding sites Biological Psychiatry 28 2 99 109 doi 10 1016 0006 3223 90 90627 E PMID 1974152 S2CID 25608914 Barnes NM Costall B Domeney AM et al September 1991 The effects of umespirone as a potential anxiolytic and 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actions Japanese Journal of Pharmacology 53 3 321 9 doi 10 1254 jjp 53 321 PMID 1975278 Kato T Hirose A Ohno Y Shimizu H Tanaka H Nakamura M December 1990 Binding profile of SM 9018 a novel antipsychotic candidate Japanese Journal of Pharmacology 54 4 478 81 doi 10 1254 jjp 54 478 PMID 1982326 Odagaki Y Toyoshima R 2007 5 HT1A receptor agonist properties of antipsychotics determined by 35S GTPgammaS binding in rat hippocampal membranes Clinical and Experimental Pharmacology amp Physiology 34 5 6 462 6 doi 10 1111 j 1440 1681 2007 04595 x PMID 17439416 S2CID 22450517 Roth BL Tandra S Burgess LH Sibley DR Meltzer HY August 1995 D4 dopamine receptor binding affinity does not distinguish between typical and atypical antipsychotic drugs Psychopharmacology 120 3 365 8 doi 10 1007 BF02311185 PMID 8524985 S2CID 13549491 Herrick Davis K Grinde E Teitler M October 2000 Inverse agonist activity of atypical antipsychotic drugs at human 5 hydroxytryptamine2C receptors The Journal of Pharmacology and Experimental Therapeutics 295 1 226 32 PMID 10991983 Rauly Lestienne I Boutet Robinet E Ailhaud MC Newman Tancredi A Cussac D October 2007 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 Naunyn Schmiedeberg s Archives of Pharmacology 376 1 2 93 105 doi 10 1007 s00210 007 0182 6 PMID 17786406 S2CID 29337002 Itzhak Y Ruhland M Krahling H February 1990 Binding of umespirone to the sigma receptor evidence for multiple affinity states Neuropharmacology 29 2 181 4 doi 10 1016 0028 3908 90 90058 Y PMID 1970425 S2CID 54326248 Kennett GA Dourish CT Curzon G February 1987 Antidepressant like action of 5 HT1A agonists and conventional antidepressants in an animal model of depression European Journal of Pharmacology 134 3 265 74 doi 10 1016 0014 2999 87 90357 8 PMID 2883013 Blier P Ward NM February 2003 Is there a role for 5 HT1A agonists in the treatment of depression Biological Psychiatry 53 3 193 203 doi 10 1016 S0006 3223 02 01643 8 PMID 12559651 S2CID 23792607 Robinson DS Rickels K Feighner J et al June 1990 Clinical effects of the 5 HT1A partial agonists in depression a composite analysis of buspirone in the treatment of depression Journal of Clinical Psychopharmacology 10 3 Suppl 67S 76S doi 10 1097 00004714 199006001 00013 PMID 2198303 S2CID 7849957 Bielski RJ Cunningham L Horrigan JP Londborg PD Smith WT Weiss K April 2008 Gepirone extended release in the treatment of adult outpatients with major depressive disorder a double blind randomized placebo controlled parallel group study The Journal of Clinical Psychiatry 69 4 571 7 doi 10 4088 jcp v69n0408 PMID 18373383 S2CID 39524249 a b Koek W Patoiseau JF Assie MB et al October 1998 F 11440 a potent selective high efficacy 5 HT1A receptor agonist with marked anxiolytic and antidepressant potential The Journal of Pharmacology and Experimental Therapeutics 287 1 266 83 PMID 9765347 a b Koek W Vacher B Cosi C et al May 2001 5 HT1A receptor activation and antidepressant like effects F 13714 has high efficacy and marked antidepressant potential European Journal of Pharmacology 420 2 3 103 12 doi 10 1016 S0014 2999 01 01011 1 PMID 11408031 a b Prinssen EP Colpaert FC Koek W October 2002 5 HT1A receptor activation and anti cataleptic effects high efficacy agonists maximally inhibit haloperidol induced catalepsy European Journal of Pharmacology 453 2 3 217 21 doi 10 1016 S0014 2999 02 02430 5 PMID 12398907 a b Maurel JL Autin JM Funes P Newman Tancredi A Colpaert F Vacher B October 2007 High efficacy 5 HT1A agonists for antidepressant treatment a renewed opportunity Journal of Medicinal Chemistry 50 20 5024 33 doi 10 1021 jm070714l PMID 17803293 Holland RL Wesnes K Dietrich B 1994 Single dose human pharmacology of umespirone European Journal of Clinical Pharmacology 46 5 461 8 doi 10 1007 bf00191912 PMID 7957544 S2CID 12117650 US patent 5431922 Nicklasson AGM Method for administration of buspirone issued 1995 07 11 assigned to Bristol Myers Squibb Company url http www google com patents US5431922 a b Manahan Vaughan D Anwyl R Rowan MJ December 1995 The azapirone metabolite 1 2 pyrimidinyl piperazine depresses excitatory synaptic transmission in the hippocampus of the alert rat via 5 HT1A receptors European Journal of Pharmacology 294 2 3 617 24 doi 10 1016 0014 2999 95 00605 2 PMID 8750726 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 Neuropharmacology 30 7 691 701 doi 10 1016 0028 3908 91 90176 C PMID 1681447 S2CID 44297577 Loscher W Witte U Fredow G Traber J Glaser T September 1990 The behavioural responses to 8 OH DPAT ipsapirone and the novel 5 HT1A receptor agonist Bay Vq 7813 in the pig Naunyn Schmiedeberg s Archives of Pharmacology 342 3 271 7 doi 10 1007 bf00169437 PMID 2149168 S2CID 24769939 Zuideveld KP Rusic Pavletic 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 7 doi 10 1124 jpet 102 036798 PMID 12438536 S2CID 14139919 Retrieved from https en wikipedia org w index php title Azapirone amp oldid 1215888946, wikipedia, wiki, book, books, library,

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