Azapirones are a class ofdrugs used asanxiolytics,antidepressants, andantipsychotics.[1][2][3][4] They are commonly used asadd-ons to otherantidepressants, such asselective serotonin reuptake inhibitors (SSRIs).[5][6][7][8][9][10]
The azapirones include the following agents:[11]
Azapirones have shown benefit in general anxiety[14] and augmenting SSRIs in social anxiety[15] and depression.[16] Evidence is not clear forpanic disorder[17] andfunctional gastrointestinal disorders.[18]
Tandospirone has also been used to augment antipsychotics inJapan as it improvescognitive andnegative symptoms ofschizophrenia.[19]Buspirone is being investigated for this purpose as well.[20][21]
Side effects of azapirones may includedizziness,headaches,restlessness,nausea, anddiarrhea.[4][22]
Azapirones have more tolerable adverse effects than many other available anxiolytics, such asbenzodiazepines or SSRIs. Unlike benzodiazepines, azapirones lackabuse potential and are notaddictive, do not causecognitive/memory impairment orsedation, and do not appear to induce appreciabletolerance orphysical dependence. However, azapirones are considered less effective with slow onset in controlling symptoms.[23]
Buspirone was originally classified as anazaspirodecanedione, shortened to azapirone or azaspirone due to the fact that itschemical structure contained thismoiety, 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 alsopyrimidinylpiperazines, though again this does not apply to them all.
Drugs classed as azapirones can be identified by their -spirone or -pirone suffix.[24]
On apharmacological level, azapirones varyingly possess activity at the followingreceptors:[25][26][27][28][29][30][31][32]
Actions atD4,5-HT2C,5-HT7, andsigma 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 ofschizophrenia (as with perospirone and tiospirone), all of them except 5-HT1A agonism are generally undesirable in anxiolytics and only contribute toside effects. As a result, further development has commenced to bring moreselective of anxiolytic agents to the market. An example of this initiative isgepirone, which was recently approved after completingclinical trials in theUnited States for the treatment ofmajor depression andgeneralized anxiety disorder. Another example istandospirone 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 inrodent 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 highintrinsic 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, inpreclinical studies, eptapirone produces robust antidepressant effects which surpass those of even high doses ofimipramine andparoxetine.[41][42][43][44]
| 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 |
Azapirones are poorly but nonetheless appreciablyabsorbed and have a rapidonset of action, but have only very shorthalf-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] Anextended release formulation of gepirone is currently under development and if approved, should help to improve this issue.
Metabolism of azapirones occurs in theliver and they areexcreted inurine andfeces. A commonmetabolite of several azapirones includingbuspirone,gepirone,ipsapirone,revospirone, andtandospirone is1-(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]