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Functional characterization of the novel antipsychotic iloperidone at human D2, D3, α2C, 5-HT6, and 5-HT1Areceptors

Authors
Journal
Life Sciences
0024-3205
Publisher
Elsevier
Publication Date
Volume
73
Issue
9
Identifiers
DOI: 10.1016/s0024-3205(03)00419-3
Keywords
  • Iloperidone
  • Atypical Antipsychotic
  • Schizophrenia
  • Psychotic Disorders

Abstract

Abstract Iloperidone has demonstrated an interesting monoamine receptor profile in radioligand binding studies, with nanomolar affinity for certain noradrenaline, dopamine, and serotonin receptors. In this study, the agonist/antagonist activity of iloperidone was determined in cell lines expressing recombinant human D 2A, D 3, α 2C, 5-HT 1A, or 5-HT 6 receptors. With the exception of 5-HT 6 receptors, these receptors are negatively coupled to cyclase. Thus, after stimulation with forskolin, the agonists dopamine (at D 2A and D 3), noradrenaline (at α 2C), or 8-OH-DPAT (at 5-HT 1A) induced a reduction in cAMP accumulation. Conversely, activation of the 5-HT 6 receptor by 5-HT led to an increase in cAMP accumulation. Iloperidone alone was devoid of significant agonist activity but inhibited the agonist response in all 5 cell lines in a surmountable and concentration-dependent fashion. Iloperidone was most potent at D 3 receptors (pK B 8.59 ± 0.20; n = 6), followed by α 2C (pK B 7.83 ± 0.06; n = 15), 5-HT 1A (pK B 7.69 ± 0.18; n = 10), D 2A (pK B 7.53 ± 0.04; n = 11) and 5-HT 6 (pK B 7.11 ± 0.08; n = 11) receptors.

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