Pharmacodynamics On a
pharmacological level, azapirones 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 azapirones. 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. 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. Indeed, in
preclinical studies, eptapirone produces robust antidepressant effects which surpass those of even high doses of
imipramine and
paroxetine. 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 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). 1-PP possesses 5-HT1A partial agonist and α2-adrenergic antagonist actions and likely contributes overall mostly to side effects. == References ==