Amisulpride

Amisulpride is an atypical antagonist of dopamine D2/D3 receptor with Ki values of 2.8±0.4nM and 3.2±0.3nM for D2 and D3 receptor subtypes, respectively [1].

Amisulpride has shown high affinity to the cloned and stably transfected human dopamine D2 with Ki values of 2.8±0.4nM and 3.2±0.3nM for D2 and D3 receptor subtypes, respectively. Amisulpride has been reported to inhibit radioligand binding to native dopamine D2 receptor in membranes from the rat striatum with an IC50 value of 21nM. Besides, Amisulpride has been revealed to displace [3H]raclopride binding in vivo with an ED50 value of 17.3±1.86mg/kg in the rat limbic system. In addition, Amisulpride has been noted to inhibit quinpirole-induced [3H]thymidine with an IC50 value of 22±3nM [1].

References:
[1] Schoemaker H1, Claustre Y, Fage D, Rouquier L, Chergui K, Curet O, Oblin A, Gonon F, Carter C, Benavides J, Scatton B. Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity. J Pharmacol Exp Ther. 1997 Jan;280(1):83-97.

Measurement of Clozapine, Norclozapine, and Amisulpride in Plasma and in Oral Fluid Obtained Using 2 Different Sampling Systems.[Pubmed:28125503]

Ther Drug Monit. 2017 Apr;39(2):109-117.

BACKGROUND: There is a poor correlation between total concentrations of proton-accepting compounds (most basic drugs) in unstimulated oral fluid and in plasma. The aim of this study was to compare clozapine, norclozapine, and Amisulpride concentrations in plasma and in oral fluid collected using commercially available collection devices [Thermo Fisher Scientific Oral-Eze and Greiner Bio-One (GBO)]. METHODS: Oral-Eze and GBO samples and plasma were collected in that order from patients prescribed clozapine. Analyte concentrations were measured by liquid chromatography-tandem mass spectrometry. RESULTS: There were 112 participants [96 men, aged (median, range) 47 (21-65) years and 16 women, aged 44 (21-65) years]: 74 participants provided 2 sets of samples and 7 provided 3 sets (overall 2 GBO samples not collected). Twenty-three patients were co-prescribed Amisulpride, of whom 17 provided 2 sets of samples and 1 provided 3 sets. The median (range) oral fluid within the GBO samples was 52 (13%-86%). Nonadherence to clozapine was identified in all 3 samples in one instance. After correction for oral fluid content, analyte concentrations in the GBO and Oral-Eze samples were poorly correlated with plasma clozapine and norclozapine (R = 0.57-0.63) and plasma Amisulpride (R = 0.65-0.72). Analyte concentrations in the 2 sets of oral fluid samples were likewise poorly correlated (R = 0.68-0.84). Mean (SD) plasma clozapine and norclozapine were 0.60 (0.46) and 0.25 (0.21) mg/L, respectively. Mean clozapine and norclozapine concentrations in the 2 sets of oral fluid samples were similar to those in plasma (0.9-1.8 times higher), that is, approximately 2- to 3-fold higher than those in unstimulated oral fluid. The mean (+/-SD) Amisulpride concentrations (microgram per liter) in plasma (446 +/- 297) and in the Oral-Eze samples (501 +/- 461) were comparable and much higher than those in the GBO samples (233 +/- 318). CONCLUSIONS: Oral fluid collected using either the GBO system or the Oral-Eze system cannot be used for quantitative clozapine and/or Amisulpride therapeutic drug monitoring.

Crystal structures and physicochemical properties of amisulpride polymorphs.[Pubmed:28371719]

J Pharm Biomed Anal. 2017 Jun 5;140:252-257.

The purpose of this work was to investigate the crystal structures and physicochemical properties of Amisulpride polymorphs. Except of the previously reported polymorph (named as Form I), a new polymorphic form (named as Form II) was discovered through comprehensive solid-state screening experiments. Both polymorphic forms were characterized by single crystal X-ray structure analysis (SXRD), powder X-ray diffraction (PXRD), dynamic vapor sorption (DVS) and thermal analysis (TGA and DSC) as well. It has been found that the Forms I and II are of conformational polymorph with the main conformational difference around ethylsulfonyl group. Form II possesses lower hygroscopicity and better solubility compared with that of Form I, indicating Form II could be an alternate solid form for formulation development.

rs7968606 polymorphism of ANKS1B is associated with improvement in the PANSS general score of schizophrenia caused by amisulpride.[Pubmed:28332719]

Hum Psychopharmacol. 2017 Mar;32(2).

A recent genome-wide pharmacogenomics study showed that the rs7968606 single-nucleotide polymorphism (SNP) of the ankyrin repeat and sterile alpha motif domain-containing protein 1B (ANKS1B) gene approached the threshold of statistical significance. The aim of this study was to determine the association between the rs7968606 SNP of ANKS1B and the treatment response to Amisulpride in schizophrenia patients. In total, 154 participants were enrolled from six university hospitals in Korea. All the subjects were interviewed before and after 6 weeks of Amisulpride treatment with the aid of the positive and negative syndrome scale and the clinical global impression-severity scale. Genotyping for the rs7968606 SNP of ANKS1B was performed in 101 subjects. Both the decrease (t = -2.067, p = 0.041) and improvement rate (t = -1.990, p = 0.049) in the positive and negative syndrome scale general score differed significantly between T-allele carriers and noncarriers of this polymorphism after 6 weeks of Amisulpride treatment. To the best of our knowledge, this is the first genetic association study of the relationship between the rs7968606 SNP of ANKS1B and the response of schizophrenia patients to treatment with Amisulpride. Future larger-scale studies involving more SNPs of ANKS1B will improve the understanding of the pharmacogenetics underlying the treatment responses to Amisulpride.

Sulpiride, Amisulpride, Thioridazine, and Olanzapine: Interaction with Model Membranes. Thermodynamic and Structural Aspects.[Pubmed:28375612]

ACS Chem Neurosci. 2017 Jul 19;8(7):1543-1553.

Neuroleptic drugs are widely applied in effective treatment of schizophrenia and related disorders. The lipophilic character of neuroleptics means that they tend to accumulate in the lipid membranes, impacting their functioning and processing. In this paper, the effect of four drugs, namely, thioridazine, olanzapine, sulpiride, and Amisulpride, on neutral and negatively charged lipid bilayers was examined. The interaction of neuroleptics with lipids and the subsequent changes in the membrane physical properties was assessed using several complementary biophysical approaches (isothermal titration calorimetry, electron paramagnetic resonance spectroscopy, dynamic light scattering, and zeta potential measurements). We have determined the thermodynamic parameters, that is, the enthalpy of interaction and the binding constant, to describe the interactions of the investigated drugs with model membranes. Unlike thioridazine and olanzapine, which bind to both neutral and negatively charged membranes, Amisulpride interacts with only the negatively charged one, while sulpiride does not bind to any of them. The mechanism of olanzapine and thioridazine insertion into the bilayer membrane cannot be described merely by a simple molecule partition between two different phases (the aqueous and the lipid phase). We have estimated the number of protons transferred in the course of drug binding to determine which of its forms, ionized or neutral, binds more strongly to the membrane. Finally, electron paramagnetic resonance results indicated that the drugs are localized near the water-membrane interface of the bilayer and presence of a negative charge promotes their burying deeper into the membrane.

Psychopharmacological profile of amisulpride: an antipsychotic drug with presynaptic D2/D3 dopamine receptor antagonist activity and limbic selectivity.[Pubmed:8996184]

J Pharmacol Exp Ther. 1997 Jan;280(1):73-82.

Amisulpride, a benzamide derivative, is an antipsychotic drug with a pharmacological profile distinct from that of classical neuroleptics such as haloperidol and from that of another benzamide, remoxipride. In mice, Amisulpride antagonized hypothermia induced by apomorphine, quinpirole or (+/-) 7-hydroxy-2-(di-n-propylamino)-tetralin, an effect involving D2/D3 receptors, at similar doses (ED50 approximately 2 mg/kg i.p.), which were much lower than doses that blocked apomorphine-induced climbing, an effect involving postsynaptic D2 and D1 receptor activation (ED50 = 21 mg/kg i.p.). Much higher doses (ED50 = 54 mg/kg i.p.) of Amisulpride were needed to block grooming behavior observed after a short period in water, a D1 receptor-mediated behavior. In rats, Amisulpride preferentially inhibited effects produced by low doses of apomorphine (hypomotility and yawning), related to stimulation of presynaptic D2/D3 dopamine autoreceptors (ED50 = 0.3 and 0.19 mg/kg i.p.). By contrast, Amisulpride antagonized apomorphine-induced hypermotility, a postsynaptic dopamine receptor-mediated effect, at a much higher dose (ED50 = 30 mg/kg i.p.). Amisulpride (100 mg/kg i.p.) only partially inhibited apomorphine-induced stereotypies (gnawing) and had no effect on stereotypies induced by d-amphetamine. However, d-amphetamine-induced hyperactivity was antagonized by doses of Amisulpride as low as 3 mg/kg i.p., which may indicate selectivity of this drug for limbic dopaminergic mechanisms. In addition, in contrast to haloperidol or remoxipride, which produced catalepsy at doses 2 or 3 times higher than those that antagonized stereotypies induced by apomorphine, Amisulpride did not induce catalepsy up to a dose of 100 mg/kg i.p., which occupies 80% of striatal D2 receptors. This pharmacological profile of Amisulpride, characterized by a preferential blockade of effects involving presynaptic mechanisms and limbic structures, may explain the clinical efficacy of this drug against both negative and positive symptoms of schizophrenia and its low propensity to produce extrapyramidal side effects.

Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity.[Pubmed:8996185]

J Pharmacol Exp Ther. 1997 Jan;280(1):83-97.

The benzamide derivative Amisulpride shows a unique therapeutic profile being antipsychotic, at high doses, and disinhibitory, at low doses, while giving rise to only a low incidence of extrapyramidal side effects. In vitro, Amisulpride has high affinity and selectivity for the human dopamine D2 (Ki = 2.8 nM) and D3 (Ki = 3.2 nM) receptors. Amisulpride shows antagonist properties toward D3 and both pre- and postsynaptic D2-like dopamine receptors of the rat striatum or nucleus accumbens in vitro. At low doses (< or = 10 mg/kg) Amisulpride preferentially blocks presynaptic dopamine autoreceptors that control dopamine synthesis and release in the rat, whereas at higher doses (40-80 mg/kg) postsynaptic dopamine D2 receptor occupancy and antagonism is apparent. In contrast, haloperidol is active in all of these paradigms within the same dose range. Amisulpride preferentially inhibits in vivo binding of the D2/D3 antagonist [3H]raclopride to the limbic system (ID50 = 17 mg/kg) in comparison to the striatum (ID50 = 44 mg/kg) of the rat, increases striatal and limbic tissue 3,4-dihydroxyphenylacetic acid levels with similar potency and efficacy, and preferentially increases extracellular 3,4-dihydroxyphenylacetic acid levels in the nucleus accumbens when compared to the striatum. Haloperidol shows similar potency for the displacement of in vivo [3H]raclopride binding in striatal and limbic regions and preferentially increases striatal tissue 3,4-dihydroxyphenylacetic acid levels. The present data characterize Amisulpride as a specific dopamine receptor antagonist with high and similar affinity for the dopamine D2 and D3 receptor. In vivo, it displays a degree of limbic selectivity and a preferential effect, at low doses, on dopamine D2/D3 autoreceptors. This atypical profile may explain the therapeutic efficacy of Amisulpride in the treatment of both positive and negative symptoms of schizophrenia.