5-HT_1A Receptor ( pKi = 14 nM ); 5-HT_1B Receptor ( pKi = 14 nM ); 5-HT_2A Receptor ( pKi = 14 nM );
5-HT_2B Receptor ( pKi = 14 nM ); 5-HT_2C Receptor ( pKi = 14 nM ); 5-HT₅ Receptor ( pKi = 14 nM );
5-HT₅ Receptor ( pKi = 14 nM ); 5-HT₇ Receptor ( pKi = 14 nM ); Alpha-2A adrenergic receptor ( pKi = 14 nM );
α1-adrenergic receptor ( pKi = 14 nM ); Alpha-2B adrenergic receptor ( pKi = 14 nM ); Alpha-2C adrenergic receptor ( pKi = 14 nM );
D₁ Receptor ( pKi = 14 nM ); D₂ Receptor ( pKi = 14 nM ); D₃ Receptor ( pKi = 14 nM );
D₄ Receptor ( pKi = 14 nM ); H₁ Receptor ( pKi = 14 nM ); H₂ Receptor ( pKi = 14 nM )
Asenapine targets multiple neurotransmitter receptors, acting as an antagonist at serotonin (5-HT), dopamine (D2), adrenergic (α1, α2), and histamine (H1, H2) receptors. It exhibits high affinity (pKi values) for these receptors: 5-HT1A (8.6), 5-HT2A (10.5), 5-HT2B (9.3), 5-HT2C (10.5), 5-HT6 (8.0), 5-HT7 (8.5), D1 (8.9), D2 (8.9), D3 (9.4), D4 (9.0), α1 (8.9), α2A (8.9), α2B (9.5), α2C (8.9), H1 (9.0), and H2 (8.2). It has much lower affinity for muscarinic receptors (pKi <5).

Asenapine exhibits high affinity and distinct rank order binding affinities (pKi) for the following receptor types: adrenoceptors (alpha1 [8.9], alpha2A [8.9], alpha2B [9.5] and alpha2C [8.9]), dopamine receptors (D1 [8.9], D2 [8.9], D3 [9.4] and D4 [9.0]), histamine receptors (H1 [9.0] and H2 [8.2]). The higher affinity of asenapine for 5-HT2C, 5-HT2A, 5-HT2B, 5-HT7, 5-HT6, alpha2B, and D3 receptors suggests that these targets will be more strongly engaged at therapeutic doses. It has been observed that asenapine exhibits potent antagonist (pKB) behavior at 5-HT1A (7.4), 5-HT1B (8.1), 5-HT2A (9.0), 5-HT2B (9.3), 5-HT2C (9.0), 5-HT6 (8.0), 5-HT7 (8.5), D2 (9.1), D3 (9.1), alpha2A (7.3), alpha2B (8.3), alpha2C (6.8), and H1 (8.4) receptors.
In vitro, asenapine exhibits high affinity and distinct rank order binding affinities for serotonin, dopamine, histamine, and adrenoceptors. It behaves as a potent antagonist at 5-HT2A (pKB=9.0), dopamine D2 (pKB=9.1), and α2-adrenoceptors. The higher affinity for 5-HT2C, 5-HT2A, 5-HT2B, 5-HT7, 5-HT6, α2B, and D3 receptors suggests that these targets are more strongly engaged at therapeutic doses. In animal models, it has shown potent antipsychotic activity.

Asenapine (0.05-0.2 mg/kg; s.c.) does not cause catalepsy; instead, it suppresses the conditioned avoidance response (CAR) in a dose-dependent manner[2].

The in vitro receptor binding assay for asenapine typically involves radioligand displacement studies using membrane preparations from cells expressing various human receptors. The compound's affinity (pKi) is determined by measuring its ability to displace specific radiolabeled ligands from serotonin (5-HT1A, 5-HT2A, 5-HT2C, etc.), dopamine (D1, D2, D3, D4), adrenergic (α1, α2A, α2B, α2C), and histamine (H1, H2) receptors. These cell-free assays provide a direct measure of the compound's binding affinity and selectivity.

In vitro cellular assays for asenapine assess its functional antagonist activity at various receptors. Cells expressing specific receptors are stimulated with appropriate agonists, and the compound's ability to inhibit downstream signaling is measured. For example, its antagonist activity at 5-HT2A, D2, and α2-adrenoceptors is confirmed in functional assays (pKB values). These assays demonstrate that asenapine acts as an antagonist at its target receptors in a functional cellular context.

Mice: 0.1 or 0.3mg/kg; Rats: 1 mL/kg, injections
Rats: Asenapine maleate is given in a volume of 1 mL/kg body weight, suspended in 10% hydroxypropyl-β-cyclodextrin. Rats are individually trained to fear by putting them in a Skinner box with an electrical foot shock. Thirty minutes prior to the assessment of freezing behavior, animals receive an intraperitoneal (i.p.) injection of asenapine, clozapine, olanzapine, buspirone, or SB242084.

Mice: The male ICR mice undergo repeated injections of asenapine at doses of 0.1 or 0.3 mg/kg. Following treatment, the mice are subjected to a battery of anxiety-related behavioral tests, such as the elevated plus-maze (EPM), defensive marble burying, open-field test, and hyponeophagia test.
In vivo animal studies for asenapine have been conducted in animal models thought to have predictive validity for antipsychotic potential. These include the apomorphine-induced climbing test (ED50 = 0.02-0.04 mg/kg s.c.) and other models. The compound's activity in these models confirms its antipsychotic efficacy. The FDA approval for bipolar mania and schizophrenia is based on clinical trials in humans.

Absorption, Distribution and Excretion
Following a single 5 mg dose, the peak plasma concentration (Cmax) is 4 ng/mL (within 1 hour); sublingual bioavailability is 35%; oral (swallowed) bioavailability is <2%; the time required to reach steady-state plasma concentrations from a 5 mg dose is 3 days; peak plasma concentrations occur within 0.5 to 1.5 hours. Doubling the asenapine dose results in a 1.7-fold increase in maximum concentration and exposure. Drinking water within 2–5 minutes after asenapine administration reduces drug exposure. Urine (50%) and feces (50%) 20–25 L/kg Due to the low oral bioavailability (less than 2%) and extensive first-pass metabolism of asenapine, sublingual administration is preferred. After sublingual administration, the drug is rapidly absorbed through the sublingual, supralingual, and buccal mucosa, with peak plasma concentrations reached within 0.5–1.5 hours.
The absolute bioavailability of sublingual asenapine (5 mg) is 35%. Steady-state plasma concentrations are reached within 3 days with twice-daily sublingual administration.
After a single 5 mg dose of asenapine, the mean Cmax is approximately 4 ng/mL, and the mean tmax is 1 hour.
For more complete data on the absorption, distribution, and excretion of asenapine (16 in total), please visit the HSDB record page.
Metabolism/Metabolites

Asenapine is oxidized by CYP1A2 and directly glucuroninated via UGT1A4. CYP1A2 oxidation is the main metabolic pathway of asenapine.
Approximately 50% of circulating metabolites in plasma have been identified. The main metabolite is asenapine N+-glucuronide; other metabolites include N-desmethylasenapine, N-desmethylasenapine N-carbamoylglucuronide, and a small amount of unmetabolized asenapine. Asenapine's activity is primarily derived from its parent drug. This study investigated the metabolism and excretion of asenapine [(3aRS,12bRS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]-oxacycloheptan[4,5-c]pyrrole(2Z)-2-butenedielate (1:1)] after sublingual administration of 14C-asenapine in healthy male volunteers. Metabolic profiles in plasma, urine, and feces were determined using high-performance liquid chromatography-radioactivity assay (HPLC-RFA). Approximately 50% of drug-related substances in human plasma were identified or quantified. The remaining circulating radioactivity corresponded to at least 15 highly polar minor peaks (primarily phase II metabolites). Overall, over 70% of circulating radioactivity was associated with bound metabolites. The main metabolic pathways were direct glucuronidation and N-demethylation. The primary circulating metabolite is asenapine N(+)-glucuronide; other circulating metabolites include N-demethylasenapine-N-carbamoyl-glucuronide, N-demethylasenapine, and asenapine 11-O-sulfate. Besides the parent compound asenapine, the primary excretory metabolite is also asenapine N(+)-glucuronide. Other excretory metabolites include N-demethylasenapine-N-carbamoyl-glucuronide, 11-hydroxyasenapine and its conjugates, 10,11-dihydroxy-N-demethylasenapine, 10,11-dihydroxyasenapine and its conjugates (several combinations of these pathways have been found), N-formylasenapine and its various hydroxylated products, and most likely, asenapine N-oxide and its 10,11-hydroxylated products and conjugates. In summary, asenapine is metabolized extensively and rapidly, producing a variety of regioisomeric hydroxylated and conjugated metabolites.

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Biological Half-Life
24 hours (range 13.4 - 39.2 hours)
After the initial rapid distribution phase, the average terminal half-life is approximately 24 hours.

Asenapine is available as a sublingual tablet (Saphris, Sycrest) for oral administration. It undergoes extensive first-pass metabolism and has a relatively short half-life. The sublingual route is used to improve bioavailability. The compound is metabolized primarily by CYP1A2 and UGT1A4. Its pharmacokinetic properties support twice-daily dosing. Asenapine has low weight gain liability compared to other atypical antipsychotics.

Hepatotoxicity
Liver function abnormalities occur in 1% to 2.5% of patients taking asenapine, but the incidence is similar in the placebo group (0.6% to 1.3%) and the control group. Elevated ALT levels are usually mild and transient, and often resolve spontaneously without dose adjustment or discontinuation. One case report showed a patient developing cholestatic serum enzyme elevations 3 to 4 weeks after starting asenapine, which returned to normal within one month after discontinuation. Therefore, asenapine may be a rare cause of mild cholestatic liver injury. Probability score: D (likely a rare cause of clinically significant liver injury). Use during pregnancy and lactation ◉ Overview of use during lactation There is currently no information regarding the use of asenapine during lactation. If a mother needs to take asenapine, she should not stop breastfeeding. However, especially when breastfeeding a newborn or premature infant, alternative medications may be preferred.
◉ Effects on Breastfed Infants
Patients taking second-generation antipsychotics while breastfeeding (n = 576) registered with the National Atypical Antipsychotics Pregnancy Registry were compared with a control group of breastfeeding patients not taking second-generation antipsychotics (n = 818). Among patients taking second-generation antipsychotics, 60.4% were concurrently taking more than one psychotropic medication. A review of pediatric medical records showed no adverse reactions in infants, regardless of whether they had received second-generation antipsychotic monotherapy or combination therapy. No cases of women taking asenapine were reported.
◉ Effects on Lactation and Breast Milk
According to the manufacturer, galactorrhea may occur with asenapine. Hyperprolactinemia appears to be the cause of galactorrhea. Hyperprolactinemia is caused by the drug's dopamine blocking effect on the tuberous-infundibular pathway. For mothers who have established lactation, their prolactin levels may not affect their ability to breastfeed.
Patients registered with the National Registry for Atypical Antipsychotic Pregnancy who were breastfeeding and taking second-generation antipsychotics (n = 576) were compared with a control group of breastfeeding patients primarily diagnosed with major depressive disorder and anxiety disorder (n = 818), who typically received selective serotonin reuptake inhibitors (SSRIs) or selective serotonin and norepinephrine reuptake inhibitors (SNRIs) but did not use second-generation antipsychotics. Among the women taking second-generation antipsychotics, 60.4% were also taking more than one psychotropic medication, compared to 24.4% in the control group. Among the women taking second-generation antipsychotics, 59.3% reported having breastfed, compared to 88.2% in the control group. At 3 months postpartum, 23% of the women taking second-generation antipsychotics were exclusively breastfeeding, compared to 47% in the control group. The number of women taking asenapine was not reported.

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Protein Binding Rate
95% protein bindingDrug Interactions
Potential drug interactions (may interfere with thermoregulation); Asenapine should be used with caution in patients taking drugs with anticholinergic activity.
Potential drug interactions (cumulative effects of central nervous system and respiratory depression). Caution should be exercised when used in combination with other drugs that can cause central nervous system depression. Avoid alcohol consumption during asenapine treatment.
Potential drug interactions (cumulative effects of QT interval prolongation); avoid concomitant use with other drugs known to prolong the corrected QT interval (QTc), including class Ia antiarrhythmic drugs (e.g., quinidine, procainamide), class III antiarrhythmic drugs (e.g., amiodarone, sotalol), certain antipsychotics (e.g., chlorpromazine, thioridazine, haloperidol, olanzapine, pimozide, paliperidone, quetiapine, ziprasidone), certain antibiotics (e.g., gatifloxacin, moxifloxacin), and bubenazine. Because asenapine has α1-adrenergic blocking activity and may cause hypotension, the manufacturer warns that it may enhance the antihypertensive effects of certain antihypertensive drugs and other medications that can cause hypotension. Asenapine is also associated with bradycardia. The manufacturer recommends caution when using asenapine in patients taking other medications that may cause hypotension or bradycardia, and suggests considering postural monitoring of these patients. If hypotension occurs, a dose reduction of asenapine should be considered. For more complete data on drug interactions with asenapine (out of 13), please visit the HSDB record page.
Asenapine has a favorable safety profile with minimal anticholinergic and cardiovascular side effects and low weight gain. Common adverse effects include somnolence, dizziness, and extrapyramidal symptoms. It has a low risk of metabolic side effects such as weight gain and dyslipidemia compared to other atypical antipsychotics. The compound is contraindicated in patients with severe hepatic impairment. Its safety profile has been well-established in clinical trials.

[1]. Asenapine: a novel psychopharmacologic agent with a unique human receptor signature. J Psychopharmacol. 2009 Jan;23(1):65-73.

[2]. Asenapine, a novel psychopharmacologic agent: preclinical evidence for clinical effects in schizophrenia. Psychopharmacology (Berl). 2008 Feb;196(3):417-29.

Therapeutic Uses
Antipsychotic Drugs
Asenapine is indicated for the treatment of schizophrenia. The efficacy of asenapine has been demonstrated in two 6-week adult clinical trials and one maintenance therapy clinical trial. /Included on US Product Label/
Monotherapy: Asenapine is indicated for the treatment of acute manic or mixed episodes associated with bipolar I disorder. Its efficacy has been demonstrated in two 3-week adult monotherapy clinical trials. /Included on US Product Label/
Adjunctive Therapy: Asenapine may be used in combination with lithium or valproate as adjunctive therapy for the treatment of acute manic or mixed episodes associated with bipolar I disorder. Its efficacy has been demonstrated in one 3-week adult adjunctive therapy clinical trial. /Included on US Product Label/
Drug Warnings
/Black Box Warning/ Warning: Increased mortality in patients with dementia-related psychosis. Patients with dementia-related psychosis receiving antipsychotic medication have an increased risk of death. An analysis of 17 placebo-controlled trials (mean duration 10 weeks) showed that the risk of death was 1.6 to 1.7 times higher in the drug treatment group than in the placebo group. These trials primarily involved patients taking atypical antipsychotics. In typical 10-week controlled trials, the mortality rate was approximately 4.5% in the drug treatment group and approximately 2.6% in the placebo group. Although the causes of death varied, most deaths appeared to be related to cardiovascular disease (e.g., heart failure, sudden death) or infectious diseases (e.g., pneumonia). Observational studies suggest that, similar to atypical antipsychotics, treatment with conventional antipsychotics may increase mortality. The extent to which the increased mortality observed in observational studies is attributable to the antipsychotics themselves, rather than certain patient characteristics, is currently unclear. Saphris (asenapine) is not approved for the treatment of dementia-related psychosis. Asenapine maleate is contraindicated in patients with known hypersensitivity to asenapine or any component of its formulations. Anaphylactic reactions, including anaphylactic shock and angioedema, have been reported in patients receiving asenapine. From August 2009 to September 2010, the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) received 52 reports of type I hypersensitivity reactions related to asenapine. Reported symptoms included anaphylactic shock, angioedema, hypotension, tachycardia, tongue swelling, dyspnea, wheezing, and rash. Some case reports indicated more than one type of hypersensitivity reaction after taking asenapine. Some case reports indicated hypersensitivity reactions (which may include angioedema, respiratory distress, and anaphylactic shock) occurring immediately after the first dose. Symptoms improved in some patients after discontinuing asenapine, while others required hospitalization or emergency room visits and treatment intervention. In placebo-controlled studies, an increased incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks), including deaths, was observed in elderly patients with dementia-related psychosis treated with certain atypical antipsychotics (aripiperazole, olanzapine, risperidone). /Antipsychotics/
For more complete data on drug warnings for asenapine (29 in total), please visit the HSDB record page.

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Pharmacodynamics
Asenapine is a serotonin, dopamine, norepinephrine, and histamine antagonist, with stronger activity against serotonin receptors than against dopamine receptors. The sedative effect in patients is related to the antagonistic activity of asenapine against histamine receptors. Its lower incidence of extrapyramidal adverse reactions is associated with upregulation of D1 receptors. This upregulation is due to the dose-dependent effect of asenapine on glutamate transmission in the brain. It has no significant activity against muscarinic and cholinergic receptors, therefore symptoms associated with anticholinergic drug activity, such as dry mouth or constipation, are not expected to be observed. Compared to first- and second-generation antipsychotics, asenapine has a higher affinity for all of the above receptors, but a lower affinity for 5-HT1A and 5-HT1B receptors.
Asenapine (Org 5222) is an FDA-approved atypical antipsychotic for the treatment of acute mania associated with bipolar disorder and schizophrenia. It is marketed as Saphris and Sycrest. Asenapine has a unique receptor binding profile with high affinity for serotonin, dopamine, histamine, and adrenoceptors. It has minimal anticholinergic effects and low weight gain liability. The compound is used clinically and is also a valuable research tool for studying neurotransmitter systems.

C17H16CLNO

285.8

285.092

C, 71.45; H, 5.64; Cl, 12.41; N, 4.90; O, 5.60

65576-45-6

Asenapine maleate; 85650-56-2; Asenapine hydrochloride; 1412458-61-7; Asenapine citrate; 1411867-74-7

3036780

White to off-white oily liquid or waxy semi-solid

1.2±0.1 g/cm3

357.9±42.0 °C at 760 mmHg

170.2±27.9 °C

0.0±0.8 mmHg at 25°C

1.610

4.31

0

2

0

20

363

2

ClC1=CC=C2OC3=CC=CC=C3[C@@](C4)([H])[C@](CN4C)([H])C2=C1

VSWBSWWIRNCQIJ-GJZGRUSLSA-N

InChI=1S/C17H16ClNO/c1-19-9-14-12-4-2-3-5-16(12)20-17-7-6-11(18)8-13(17)15(14)10-19/h2-8,14-15H,9-10H2,1H3/t14-,15-/m0/s1

(2R,6R)-9-chloro-4-methyl-13-oxa-4-azatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),7(12),8,10,14,16-hexaene

Asenapine; (+/-)-Asenapine; Org 5222; Org-5222; Org5222

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~200 mg/mL (~699.9 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.75 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (8.75 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (8.75 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)