Pharmacodynamics +<unk>  Site Ki (nM) Species Ref σ1 0.2–50 Rodent σ2 110 ≥2,200 Rat/? ≥700 Rat/? ≥3,000 Rat/? 5-HT1A >10,000 ? 5-HT2A 120 ? 5-HT2C α1 200 ? α2 6,100 ? D1 900 Rat D2 120–300 Rat H1 6.03 Human H2 4,470 Human H3 61,700 Human H4 >100,000 Human 3,300 ? NMDA/ >30,000 Rat Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.<unk>  acts as a high affinity sigma receptor agonist, primarily of the σ1 subtype, but also of the σ2 subtype with lower affinity. In one study of σ1 receptor ligands that also included haloperidol, pentazocine, (+)-3-PPP, ditolylguanidine, dextromethorphan, SKF-10,047 ((±)-alazocine), ifenprodil, progesterone, and others,<unk>  showed the highest affinity (Ki = 0.2–0.3) for the guinea pig σ1 receptor of all the tested ligands except haloperidol, which it was approximately equipotent with. The sigma receptor agonism of<unk>  is thought to be responsible for its therapeutic benefits against anxiety and depression. Unlike other TCAs,<unk>  does not inhibit the reuptake of serotonin or norepinephrine. However, it does act as a high affinity antagonist of the histamine H1 receptor and is a low to moderate affinity antagonist of the dopamine D2, serotonin 5-HT2, and α1-adrenergic receptors. H1 receptor antagonism accounts for its antihistamine effects and associated sedative side effects. In contrast to other TCAs,<unk>  has very low affinity for the muscarinic acetylcholine receptors and virtually no anticholinergic effects. Sigma receptors are a set of proteins located in the endoplasmic reticulum. σ1 receptors play key role in potentiating intracellular calcium mobilization thereby acting as sensor or modulator of calcium signaling. Occupancy of σ1 receptors by agonists causes translocation of the receptor from endoplasmic reticulum to peripheral areas (membranes) where the σ1 receptors cause neurotransmitter release.<unk>  is said to have a biphasic action, with prompt initial improvement of tension, anxiety, and insomnia followed by improved mood later. Hence, it is an anxiolytic with an antidepressant component. After sub-chronic treatment with<unk> , σ2 receptors are significantly downregulated but σ1 receptors are not. Pharmacokinetics<unk>  is rapidly and completely absorbed by the gastrointestinal tract. The bioavailability of<unk>  amounts to 94%. After single oral administration of 50 mg, the peak plasma concentration of the drug is reached after 3.3 hours and amounts to 15.6 ng/mL. After single oral administration of 100 mg the maximum plasma concentration is reached after 3 hours and amounts to 33.2 ng/mL. Therapeutic concentrations of<unk>  range from 140 to 550 nmol/L. The plasma protein binding amounts to approximately 91% and the volume of distribution is approximately 10 L/kg.<unk>  is partially metabolized in the liver to deshydroxyethylopipramol. Metabolism occurs through the CYP2D6 isoenzyme. Its terminal half-life in plasma is 6–11 hours. About 70% is eliminated in urine with 10% unaltered. The remaining portion is eliminated through feces.
Opipramol
Stiripentol
Fenproporex
Mitapivat
Florbetapir 
Avacopan
Vigabatrin
Piritramide