Interaction of the novel antipsychotic drug amperozide and its metabolite FG5620 with central nervous system receptors and monoamine uptake sites: Relation to behavioral and clinical effects

doi:10.1016/S0006-3223(96)00117-5

Biological Psychiatry

Volume 42, Issue 4, 15 August 1997, Pages 247-259

https://doi.org/10.1016/S0006-3223(96)00117-5 Get rights and content

Behavioral, biochemical, and electrophysiological studies suggest that amperozide affects mesolimbic and mesocortical dopamine neurotransmission. The receptor binding profile of amperozide is discussed and related to behavioral and clinical, i.e., antipsychotic, effects of the drug. As previously reported, amperozide displayed high affinity for serotonin 5-HT_2A receptors (K_i = 16 nmol/L), and moderate affinity for striatal dopamine D₂ (K_i = 540 nmol/L) and cortical α₁-adrenergic receptors (K_i = 172 nmol/L). In the present study amperozide displayed low affinity for several serotonin receptor subtypes as well as for the dopamine D₄ receptor transfected in COS7 cells (K_i D_4.2 = 769 nmol/L and K_i D_4.4 = 384 nmol/L). Amperozide was very weak or did not interact with several other receptor species including adrenergic, histaminergic, muscarinic, benzodiazepine, γ-aminobutyric acid, amino acid, opiate, and Ca channels; however, amperozide was found to compete for [³H]paroxetine binding for the serotonin transporter in the nanomolar range (K_i = 49 nmol/L). In vitro and in vivo binding potency of amperozide correlates best with behavioral effects, indicating 5-HT_2A antagonism, although serotonin uptake inhibition may contribute to the effects of amperozide on dopamine neurotransmission. The metabolite of amperozide, FG5620, displayed 5–10 times lower pharmacologic activity than amperozide. These properties of amperozide may suggest that the antipsychotic effects of amperozide are mediated by 5-HT_2A receptors, although 5-HT uptake inhibition and α₁-adrenergic receptor-mediated effects may be considered, particularly at higher doses.

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Interaction of the novel antipsychotic drug amperozide and its metabolite FG5620 with central nervous system receptors and monoamine uptake sites: Relation to behavioral and clinical effects

Eur J Pharmacol

Eur J Pharmacol

Life Sci

Life Sci

Life Sci

Eur J Pharmacol

Brain Res Bull

Pharmacol Biochem Behav

Eur J Pharmacol

Pharmacol Biochem Behav

Eur J Pharmacol

Biol Psychiatry

Anal Biochem

Pharmacol Biochem Behav

Pharmacol Biochem Behav

Brain Res

Eur J Pharmacol

Eur J Pharmacol

J Neurol Sci

Life Sci

Brain Res

Effects of amperozide on the dopamine synthesis activity in the tuberoinfundibular neurons

Arzneim-Forsch/Drug Res

Negative vs. positive schizophrenia: Definition and validation

Arch Gen Psychiatry

Serotonin2 (5-HT2) receptors binding in the frontal cortex of schizophrenic patients

J Neural Transm

CPRS—The comprehensive psychopathology rating scale

Acta Psychiatr Scand Suppl

Effects of amperozide in schizophrenia—An open study of a potent 5-HT2 antagonist

Psychopharmacology (Berl)

Prefrontal dopamine and deficit symptoms in schizophrenia

A double-blind comparison of melperone and thiothixene in psychotic women using a new rating scale, the CPRS

Arch Psychiatr Nervenkr

Amperozide in the treatment of schizophrenic patients

In the search for a novel class of antipsychotic drugs: Preclinical pharmacology of FG5803, a 1-piperazinecarboxamide derivative

J Pharmacol Exp Ther

Serotonin release contributes to the locomotor stimulant effects of 3,4-methylenedioxymethamphetamine in rats

J Pharmacol Exp Ther

Potentiation of phenothiazine by methyltyrosine in treatment of chronic schizophrenia

J Neural Transm

Amperozide: A new pharmacological approach in the treatment of schizophrenia

Pharmacol Toxicol

The risks and benefits of clozapine versus chlorpromazine

J Clin Psychopharmacol

Ritanserin in the treatment of negative symptoms in chronic schizophrenic patients

Ritanserin, a selective 5-HT2/1C antagonist, and negative symptoms in schizophrenia: A placebo-controlled double-blind trial

Br J Psychiatry

Identification of amperozide metabolites in urine from rats, rabbits, dogs and man, by Frit-FAB LC/MS using deuterated solvents to gain additional structural information

J Mass Spectrometry

Amperozide and conditioned behaviour in rats: Potentiation by classical neuroleptics and α-methylparatyrosine

Pharmacol Toxicol

Effects of amperozide in two animal models of anxiety

Pharmacol Toxicol

Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine: Relation to extrapyramidal side effects

Arch Gen Psychiatry

D1-, D2-, and 5-HT2-receptor occupancy in clozapine-treated patients

J Clin Psychiatry

Depletion of brain serotonin by 5,7-dihydroxytryptamine alters the response to amphetamine and the habituation of locomotor activity in rats

Psychopharmacology (Berl)

[3H]Nitrendipine-labeled calcium channels discriminate inorganic calcium antagonists

Effects of amperozide, a putative antipsychotic drug, on rat midbrain dopamine neurons recorded in vivo

Pharmacol Toxicol

Complete conversion of brain D2 dopamine receptors from the high- to the low-affinity state for dopamine agonists, using sodium ions and guanine nucleotide

J Neurochem

Amperozide and emotional behaviour

Pharmacol Toxicol

Amperozide—A new putatively antipsychotic drug with a limbic mode of action on dopamine mediated behaviour

Pharmacol Toxicol

Differential changes in serotonin 5-HT1A and 5-HT2 receptor binding in patients with chronic schizophrenia

Psychopharmacology (Berl)

(3H)-(H-D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2)((3H)CTOP), A potent and highly selective peptide for mu opioid receptors in rat brain

J Pharmacol Exp Ther

Serotonin₂ (5-HT₂) receptors binding in the frontal cortex of schizophrenic patients

Effects of amperozide in schizophrenia—An open study of a potent 5-HT₂ antagonist

Positron emission tomographic analysis of central D₁ and D₂ dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine: Relation to extrapyramidal side effects

D₁-, D₂-, and 5-HT₂-receptor occupancy in clozapine-treated patients

[³H]Nitrendipine-labeled calcium channels discriminate inorganic calcium antagonists

Differential changes in serotonin 5-HT_1A and 5-HT₂ receptor binding in patients with chronic schizophrenia

(³H)-(H-D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2)((³H)CTOP), A potent and highly selective peptide for mu opioid receptors in rat brain