Pharmacodynamics On a pharmacological level,<unk> s varyingly possess activity at the following receptors: * 5-HT1A receptor (as partial or full agonists) * 5-HT2A receptor (as inverse agonists) * D2 receptor (as antagonists or partial agonists) * α1-adrenergic receptor (as antagonists) * α2-adrenergic receptor (as antagonists) Actions at D4, 5-HT2C, 5-HT7, and sigma receptors have also been shown for some<unk> s. 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 is currently in 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. 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. 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<unk> s which act as 5-HT1A receptor full agonists such as alnespirone and eptapirone. Indeed, in preclinical studies, eptapirone produces robust antidepressant effects which surpass those of even high doses of imipramine and paroxetine. Comparison of binding profiles + Affinities of<unk> s for Neurotransmitter Binding Sites (Ki, nM) 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 – – – > 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 38,000 ± 5,000 > 100,000 49,000 ± 5,000 > 100,000 GABAA/ > 100,000 > 100,000 > 100,000 > 100,000 Pharmacokinetics<unk> s 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. 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. An extended release formulation of gepirone is currently under development and if approved, should help to improve this issue. Metabolism of<unk> s occurs in the liver and they are excreted in urine and feces. A common metabolite of several<unk> s including buspirone, gepirone, ipsapirone, revospirone, and tandospirone is 1-(2-pyrimidinyl)piperazine (1-PP). 1-PP possesses 5-HT1A partial agonist and α2-adrenergic antagonist actions and likely contributes overall mostly to side effects.
Azapirone
Remoxipride
Xipamide
Pitolisant
Fabomotizole
Benazepril
Gepirone
Lumasiran