Iloperidone binding to human and rat dopamine and 5-HT receptors

Kongsamut, Sathapana; Roehr, Joachim E.; Cai, Jianhu; Hartman, Harold B.; Weissensee, Paul; Kerman, Lisa L.; Tang, Lei; Sandrasagra, Anthony

doi:10.1016/s0014-2999(96)00840-0

Cited by 80 publications

(51 citation statements)

References 17 publications

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“…Its affinity for human dopamine and 5-HT receptors has been reported previously (Kongsamut et al 1996). This report presents the affinity of iloperidone for a largely extended number of human neurotransmitter receptors.…”

supporting

confidence: 59%

“…In a few instances human receptors were not available and receptor studies were performed on tissues from laboratory animals. The present data, supplemented with those of Kongsamut et al (1996) The prototypical classical neuroleptic agent haloperidol is an effective antipsychotic compound (Leucht et al 1999) which, unfortunately, also induces severe extrapyramidal side effects (EPS) and hyperprolactinemia. The term "atypical antipsychotic" was originally introduced to describe compounds, such as clozapine, which not only suppressed psychotic symptoms, but differed from haloperidol by having a low tendency to induce EPS and increase plasma prolactin levels.…”

Section: Iloperidone Is a Novel Psychotropic Compound Currently Undermentioning

confidence: 66%

“…These authors suggested that therapeutic activity could be related to blockade of presynaptic D 2B receptors, whereas extrapyramidal side effects could be avoided if the compound would fail to bind to D 2A receptors. As published by Kongsamut et al (1996), iloperidone displays higher affinity for the D 2B than for the D 2A form which, according to the foregoing, would indicate a reduced propensity to cause EPS. …”

mentioning

confidence: 65%

“…The large difference of potency of iloperidone in these tests is expected to result in an improved ratio of therapeutic effect to EPS liability compared with standard antipsychotics. Previous studies have investigated the receptor binding profile of iloperidone with rat receptors ) and a limited number of human homologues of dopamine and 5-HT receptor subtypes (Kongsamut et al 1996). These experiments demonstated that iloperidone displays the desired 5-HT 2A /D 2 affinity ratio.…”

Section: Iloperidone Is a Novel Psychotropic Compound Currently Undermentioning

confidence: 99%

“…These results indicate that D 4 receptor blockade is unlikely to be a major contributor to antipsychotic activity. Although iloperidone displayed relevant affinity for the human D 4 receptor (K I 25 nM; Kongsamut et al 1996), this probably has no therapeutic consequence.Iloperidone, like most commonly used antipsychotics, has significant affinity for the dopamine D 3 receptor and is likely to interact at these sites at therapeutically relevant doses. Selective D 3 receptor antagonists have been described, but these are not yet tested in schizophrenic patients.…”

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confidence: 97%

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Extended Radioligand Binding Profile of Iloperidone A Broad Spectrum Dopamine/Serotonin/Norepinephrine Receptor Antagonist for the Management of Psychotic Disorders

Kalkman

Subramanian

Hoyer

2001

Neuropsychopharmacology

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Iloperidone is a novel psychotropic compound currently undergoing Phase III trials. Its affinity for human dopamine and 5-HT receptors has been reported previously (Kongsamut et al. 1996). This report presents the affinity of iloperidone for a largely extended number of human neurotransmitter receptors. In a few instances human receptors were not available and receptor studies were performed on tissues from laboratory animals. The present data, supplemented with those of Kongsamut et al. (1996) The prototypical classical neuroleptic agent haloperidol is an effective antipsychotic compound (Leucht et al. 1999) which, unfortunately, also induces severe extrapyramidal side effects (EPS) and hyperprolactinemia. The term "atypical antipsychotic" was originally introduced to describe compounds, such as clozapine, which not only suppressed psychotic symptoms, but differed from haloperidol by having a low tendency to induce EPS and increase plasma prolactin levels. It is postulated that dopamine D 2 receptor blockade is the mechanism by which antipsychotic activity is achieved (Creese et al. 1976;Seeman et al. 1976 Conley et al. 1999;Taylor and Duncan-McConnell 2000). The elucidation of the multiple receptor interactions of clozapine suggested that other neurotransmitter systems may also play a role in the efficacy and tolerability of that molecule. Particularly, the antiadrenergic effects of clozapine are now receiving increased attention (Nutt 1994;Litman et al. 1996;Hertel et al. 1999). Iloperidone is a new psychotropic agent currently undergoing Phase III trials for the treatment of psychotic disorders (Figure 1). Iloperidone was selected from a large series of piperidinyl-benzisoxazoles because it showed a 300-fold greater potency in a test for limbic activity (inhibition of apomorphine-induced climbing) than in a test for nigrostriatal activity (inhibition of apomorphine-induced stereotypy) . The large difference of potency of iloperidone in these tests is expected to result in an improved ratio of therapeutic effect to EPS liability compared with standard antipsychotics. Previous studies have investigated the receptor binding profile of iloperidone with rat receptors ) and a limited number of human homologues of dopamine and 5-HT receptor subtypes (Kongsamut et al. 1996). These experiments demonstated that iloperidone displays the desired 5-HT 2A /D 2 affinity ratio. The aim of the present study was to determine the receptor affinity profile of iloperidone at a wider range of human neurotransmitter receptors. In resemblance to clozapine, it was noted that iloperidone possesses high affinity for norepinephrine ␣ 1 -and ␣ 2C adrenergic receptors. METHODSThe radioligand receptor binding assays are listed in Table 1. MaterialsRadioligands were purchased from NEN Life Science Products, USA, except for 3 H-RX821002 and 3 H-Mesulergine, which were obtained from Amersham Pharmacia Biotech Ltd, UK, and 125 I-GTI which was obtained from ANAWA, Switzerland. Iloperidone was synthesized by Hoechst Marion Roussel. Unless speci...

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supporting

confidence: 59%

Section: Iloperidone Is a Novel Psychotropic Compound Currently Undermentioning

confidence: 66%

mentioning

confidence: 65%

Section: Iloperidone Is a Novel Psychotropic Compound Currently Undermentioning

confidence: 99%

mentioning

confidence: 97%

See 3 more Smart Citations

Extended Radioligand Binding Profile of Iloperidone A Broad Spectrum Dopamine/Serotonin/Norepinephrine Receptor Antagonist for the Management of Psychotic Disorders

Kalkman

Subramanian

Hoyer

2001

Neuropsychopharmacology

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Association study of the 5-HT6 receptor gene in schizophrenia

et al. 1999

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Serotonergic (5-hydroxytryptamine; 5-HT) transmission may play an important role in the treatment and/or pathogenesis of schizophrenia. Previous studies reported that several atypical antipsychotic agents have high affinities for the 5-HT6 receptor. The 5-HT6 receptor gene polymorphism might contribute to the genetic background of this disorder. One hundred and fifty unrelated patients with schizophrenia and 150 unrelated healthy controls were genotyped for a biallelic polymorphism (267C/T) at the 5-HT6 receptor gene. No significant positive association between the 5-HT6 receptor genotype and schizophrenia was observed. Our results suggests that the 267C/T polymorphism of the 5-HT6 receptor gene may not be involved in the susceptibility to schizophrenia.

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