Pharmacodynamics +<unk>  Site Ki (nM) Species Ref 5-HT1A 3.98–21421 (median) Human 5-HT1B >100,000 Rat 5-HT1D 22,000–42,700 Human 5-HT2A 138759–1,300 HumanRat 5-HT2B 214 Human 5-HT2C 4901,100–6,026 HumanRat/pig 5-HT3 >10,000 Rat 5-HT4 >10,000 Rat 5-HT6 398 Mouse 5-HT7 375–381840 RatHuman α1 1,000 Rat α2 6,000 Rat α2A 7.3 () Human β 8,800 Rat D1 33,000 Rat D2 484240 HumanRat D3 98 Human D4 29 Human 38,000 Rat GABAA() >100,000 Rat Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.<unk>  acts as an agonist of the serotonin 5-HT1A receptor with high affinity. It is a partial agonist of both presynaptic 5-HT1A receptors, which are inhibitory autoreceptors, and postsynaptic 5-HT1A receptors. It is thought that the main effects of<unk>  are mediated via its interaction with the presynaptic 5-HT1A receptor, thus reducing the firing of serotonin-producing neurons.<unk>  also has lower affinities for the serotonin 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT7 receptors. In addition to binding to serotonin receptors,<unk>  is an antagonist of the dopamine D2 receptor with weak affinity. It preferentially blocks inhibitory presynaptic D2 autoreceptors, and antagonizes postsynaptic D2 receptors only at higher doses. In accordance,<unk>  has been found to increase dopaminergic neurotransmission in the nigrostriatal pathway at low doses, whereas at higher doses, postsynaptic D2 receptors are blocked and antidopaminergic effects such as hypoactivity and reduced stereotypy, though notably not catalepsy, are observed in animals.<unk>  has also been found to bind with much higher affinity to the dopamine D3 and D4 receptors, where it is similarly an antagonist. A major metabolite of<unk> , 1-(2-pyrimidinyl)piperazine (1-PP), occurs at higher circulating levels than<unk>  itself and is known to act as a potent α2-adrenergic receptor antagonist. This metabolite may be responsible for the increased noradrenergic and dopaminergic activity observed with<unk>  in animals. In addition, 1-PP may play an important role in the antidepressant effects of<unk> .<unk>  also has very weak and probably clinically unimportant affinity for the α1-adrenergic receptor. However,<unk>  has been reported to have shown "significant and selective intrinsic efficacy" at the α1-adrenergic receptor expressed in a "tissue- and species-dependent manner". Unlike benzodiazepines,<unk>  does not interact with the GABAA receptor complex. Pharmacokinetics<unk>  has a low oral bioavailability of 3.9% relative to intravenous injection due to extensive first-pass metabolism. The time to peak plasma levels following ingestion is 0.9 to 1.5 hours. It is reported to have an elimination half-life of 2.8 hours, although a review of 14 studies found that the mean terminal half-life ranged between 2 and 11 hours, and one study even reported a terminal half-life of 33 hours.<unk>  is metabolized primarily by CYP3A4, and prominent drug interactions with inhibitors and inducers of this enzyme have been observed. Major metabolites of<unk>  include 5-hydroxybuspirone, 6-hydroxybuspirone, 8-hydroxybuspirone, and 1-PP. 6-Hydroxybuspirone has been identified as the predominant hepatic metabolite of<unk> , with plasma levels that are 40-fold greater than those of<unk>  after oral administration of<unk>  to humans. The metabolite is a high-affinity partial agonist of the 5-HT1A receptor (Ki = 25 nM) similarly to<unk> , and has demonstrated occupancy of the 5-HT1A receptor in vivo. As such, it is likely to play an important role in the therapeutic effects of<unk> . 1-PP has also been found to circulate at higher levels than those of<unk>  itself and may similarly play a significant role in the clinical effects of<unk> . Phase I Metabolism of<unk>  in humans
Buspirone
Nabilone
Dapoxetine
Medazepam
Atomoxetine
Citalopram
Sulpiride
Phenazepam