Chemistry:Azapirone

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Short description: Drug class of psycotropic drugs
Buspirone, the prototypical azapirone anxiolytic, which contains azaspirodecanedione and pyrimidinylpiperazine bound via a butyl chain.

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]

List of azapirones

The azapirones include the following agents:[11]


Anxiolytics
Antipsychotics
others


Medical uses

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

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

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

Pharmacodynamics

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

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
SERT – – – > 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
mACh 38,000 ± 5,000 > 100,000 49,000 ± 5,000 > 100,000
GABAA/BDZ > 100,000 > 100,000 > 100,000 > 100,000

Pharmacokinetics

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

  1. ↑ 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. 
  2. ↑ Cadieux RJ (May 1996). "Azapirones: an alternative to benzodiazepines for anxiety". American Family Physician 53 (7): 2349–53. PMID 8638511. 
  3. ↑ Chessick, Cheryl A, ed (2006). "Azapirones for generalized anxiety disorder". Cochrane Database of Systematic Reviews 3 (3): CD006115. doi:10.1002/14651858.CD006115. PMID 16856115. 
  4. ↑ 4.0 4.1 "Serotonin-1A anxiolytics: an overview". Psychopathology 22 Suppl 1 (1): 21–6. 1989. doi:10.1159/000284623. PMID 2567039. 
  5. ↑ "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. 
  6. ↑ 6.0 6.1 "Buspirone augmentation of selective serotonin reuptake inhibitors (SSRIs) in social phobia". Journal of Affective Disorders 39 (2): 115–21. July 1996. doi:10.1016/0165-0327(96)00030-4. PMID 8827420. 
  7. ↑ 7.0 7.1 "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. April 1997. PMID 9180827. 
  8. ↑ 8.0 8.1 "Buspirone augmentation of antidepressant therapy". Journal of Clinical Psychopharmacology 18 (6): 465–9. December 1998. doi:10.1097/00004714-199812000-00009. PMID 9864079. 
  9. ↑ 9.0 9.1 "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. June 2001. doi:10.4088/JCP.v62n0608. PMID 11465522. 
  10. ↑ 10.0 10.1 "Clinical efficacy of tandospirone augmentation in patients with major depressive disorder: a randomized controlled trial". Psychiatry and Clinical Neurosciences 57 (2): 183–7. April 2003. doi:10.1046/j.1440-1819.2003.01099.x. PMID 12667165. 
  11. ↑ "The Use of Common Stems in the Selection of International Nonproprietary Names (INN) for Pharmaceutical Substances: Alphabetical list of stems together with corresponding INNs". http://apps.who.int/medicinedocs/en/d/Js4895e/6.html. 
  12. ↑ CID 10319570 from PubChem
  13. ↑ CID 9845181 from PubChem
  14. ↑ "Azapirones for generalized anxiety disorder.". Reviews 2015 (3): CD006115. 2006. doi:10.1002/14651858.CD006115. PMID 16856115. 
  15. ↑ "Pharmacological treatment of social anxiety disorder". Anxiety Disorders. Modern Trends in Pharmacopsychiatry. 29. Sep 20, 2013. pp. 144–53. doi:10.1159/000351960. ISBN 978-3-318-02463-0. 
  16. ↑ 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. 
  17. ↑ Imai, H; Tajika, A; Chen, P; Pompoli, A; Guaiana, G; Castellazzi, M; Bighelli, I; Girlanda, F et al. (Sep 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. PMID 25268297. 
  18. ↑ "Effects on gastrointestinal functions and symptoms of serotonergic psychoactive agents used in functional gastrointestinal diseases". J Gastroenterol 48 (2): 177–81. Feb 2013. doi:10.1007/s00535-012-0726-5. PMID 23254779. 
  19. ↑ "Enhancement of cognitive performance in schizophrenia by addition of tandospirone to neuroleptic treatment". The American Journal of Psychiatry 158 (10): 1722–5. October 2001. doi:10.1176/appi.ajp.158.10.1722. PMID 11579010. 
  20. ↑ "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. September 2007. doi:10.1016/j.schres.2007.06.008. PMID 17628435. 
  21. ↑ "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. August 2009. doi:10.1002/hup.1046. PMID 19637398. 
  22. ↑ "Review of the side-effect profile of buspirone". The American Journal of Medicine 80 (3B): 17–21. March 1986. doi:10.1016/0002-9343(86)90327-X. PMID 2870641. 
  23. ↑ "Management of Generalized Anxiety Disorder in Primary Care: Identifying the Challenges and Unmet Needs". Prim Care Companion J Clin Psychiatry 12 (2). 2010. doi:10.4088/PCC.09r00772blu. PMID 20694114. 
  24. ↑ "The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances". 2004. http://libdoc.who.int/hq/2004/who_edm_qsm_2004.5.pdf. 
  25. ↑ 25.0 25.1 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. 
  26. ↑ "The effects of umespirone as a potential anxiolytic and antipsychotic agent". Pharmacology Biochemistry and Behavior 40 (1): 89–96. September 1991. doi:10.1016/0091-3057(91)90326-W. PMID 1685786. 
  27. ↑ "Mixed agonist-antagonist properties of umespirone at neostriatal dopamine receptors in relation to its behavioral effects in the rat". European Journal of Pharmacology 222 (1): 69–74. November 1992. doi:10.1016/0014-2999(92)90464-F. PMID 1361441. 
  28. ↑ "Atypicality of several antipsychotics on the basis of in vivo dopamine-D2 and serotonin-5HT2 receptor occupancy". Neuropsychopharmacology 12 (1): 57–64. February 1995. doi:10.1016/0893-133X(94)00064-7. PMID 7766287. 
  29. ↑ "5-hydroxytryptamine2A receptor inverse agonists as antipsychotics". The Journal of Pharmacology and Experimental Therapeutics 299 (1): 268–76. October 2001. PMID 11561089. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11561089. 
  30. ↑ "Pharmacological actions of SM-9018, a new neuroleptic drug with both potent 5-hydroxytryptamine2 and dopamine2 antagonistic actions". Japanese Journal of Pharmacology 53 (3): 321–9. July 1990. doi:10.1254/jjp.53.321. PMID 1975278. 
  31. ↑ "Binding profile of SM-9018, a novel antipsychotic candidate". Japanese Journal of Pharmacology 54 (4): 478–81. December 1990. doi:10.1254/jjp.54.478. PMID 1982326. 
  32. ↑ "5-HT1A receptor agonist properties of antipsychotics determined by [35S]GTPgammaS binding in rat hippocampal membranes". Clinical and Experimental Pharmacology & Physiology 34 (5–6): 462–6. 2007. doi:10.1111/j.1440-1681.2007.04595.x. PMID 17439416. 
  33. ↑ "D4 dopamine receptor binding affinity does not distinguish between typical and atypical antipsychotic drugs". Psychopharmacology 120 (3): 365–8. August 1995. doi:10.1007/BF02311185. PMID 8524985. 
  34. ↑ "Inverse agonist activity of atypical antipsychotic drugs at human 5-hydroxytryptamine2C receptors". The Journal of Pharmacology and Experimental Therapeutics 295 (1): 226–32. October 2000. PMID 10991983. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10991983. 
  35. ↑ "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. October 2007. doi:10.1007/s00210-007-0182-6. PMID 17786406. 
  36. ↑ "Binding of umespirone to the sigma receptor: evidence for multiple affinity states". Neuropharmacology 29 (2): 181–4. February 1990. doi:10.1016/0028-3908(90)90058-Y. PMID 1970425. 
  37. ↑ "Antidepressant-like action of 5-HT1A agonists and conventional antidepressants in an animal model of depression". European Journal of Pharmacology 134 (3): 265–74. February 1987. doi:10.1016/0014-2999(87)90357-8. PMID 2883013. 
  38. ↑ "Is there a role for 5-HT1A agonists in the treatment of depression?". Biological Psychiatry 53 (3): 193–203. February 2003. doi:10.1016/S0006-3223(02)01643-8. PMID 12559651. 
  39. ↑ "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. June 1990. doi:10.1097/00004714-199006001-00013. PMID 2198303. 
  40. ↑ "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. April 2008. doi:10.4088/jcp.v69n0408. PMID 18373383. 
  41. ↑ 41.0 41.1 "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. October 1998. PMID 9765347. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9765347. 
  42. ↑ 42.0 42.1 "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. May 2001. doi:10.1016/S0014-2999(01)01011-1. PMID 11408031. 
  43. ↑ 43.0 43.1 "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. October 2002. doi:10.1016/S0014-2999(02)02430-5. PMID 12398907. 
  44. ↑ 44.0 44.1 "High-efficacy 5-HT1A agonists for antidepressant treatment: a renewed opportunity". Journal of Medicinal Chemistry 50 (20): 5024–33. October 2007. doi:10.1021/jm070714l. PMID 17803293. 
  45. ↑ "Single dose human pharmacology of umespirone". European Journal of Clinical Pharmacology 46 (5): 461–8. 1994. doi:10.1007/bf00191912. PMID 7957544. 
  46. ↑ Nicklasson AGM, "Method for administration of buspirone", US patent 5431922, issued 1995-07-11, assigned to Bristol-Myers Squibb Company url=http://www.google.com/patents/US5431922
  47. ↑ 47.0 47.1 "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. December 1995. doi:10.1016/0014-2999(95)00605-2. PMID 8750726. 
  48. ↑ 48.0 48.1 "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. 
  49. ↑ "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. September 1990. doi:10.1007/bf00169437. PMID 2149168. 
  50. ↑ "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. December 2002. doi:10.1124/jpet.102.036798. PMID 12438536. 



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