Occupancy of striatal D 2 -like dopamine receptors after treatment with the sigma ligand EMD 57445, a putative atypical antipsychotic

Gründer, Gerhard; Müller, Matthias J.; Andreas, J.; Heydari, N.; Wetzel, Hermann; Schlößer, R.; Schlegel, S.; Nickel, O.; Eißner, D; Benkert, Otto

doi:10.1007/s002130051091

Cited by 20 publications

(18 citation statements)

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“…EPS could not be detected in our sample of normal volunteers, either, although Farde's hypothesis would predict severe EPS al least at the higher doses administered. The observation that high D 2 receptor occupancy may not necessarily be strictly related to EPS or even clinical efficacy was already made with the sigma ligand EMD 57445 (Gründer et al 1999). In the case of aripiprazole, its partial dopamine agonism or dopamine autoreceptor agonism, respectively, may explain our unexpected findings.…”

Section: Discussionmentioning

confidence: 98%

Dopamine D2 and D3 Receptor Occupancy in Normal Humans Treated with the Antipsychotic Drug Aripiprazole (OPC 14597) A Study Using Positron Emission Tomography and [11C]Raclopride

Yokoi

2002

Neuropsychopharmacology

279

147

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Section: Discussionmentioning

confidence: 98%

Dopamine D2 and D3 Receptor Occupancy in Normal Humans Treated with the Antipsychotic Drug Aripiprazole (OPC 14597) A Study Using Positron Emission Tomography and [11C]Raclopride

Yokoi

2002

Neuropsychopharmacology

279

147

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“…Concern for metabolite confounders is based upon prior work showing that O ‐demethylation of some σ receptor ligands by cytochrome P450 enzymes can lead to centrally active metabolites with a different spectrum of activity. The atypical antipsychotic panamesine is highly selective for σ receptors in vitro, but is converted into a phenolic metabolite that occupies striatal dopamine D 2 ‐like receptors as observed by single photon emission computed tomography (SPECT) imaging studies in human beings (Gründer et al, ). To cite another instance, the major phenolic metabolite of ibogaine shows reduced affinity for σ 2 receptors, and 3‐ to 20‐fold higher affinity for the DAT and SERT, respectively (Baumann et al, ).…”

Section: Discussionmentioning

confidence: 99%

A selective sigma‐2 receptor ligand antagonizes cocaine‐induced hyperlocomotion in mice

Lever

Miller

Green

et al. 2013

Synapse

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Cocaine functions, in part, through agonist actions at sigma-1 (σ1 ) receptors, while roles played by sigma-2 (σ2 ) receptors are less established. Attempts to discriminate σ2 receptor-mediated effects of cocaine in locomotor hyperactivity assays have been hampered by the lack of potent and selective antagonists. Certain tetrahydroisoquinolinyl benzamides display high σ2 receptor affinity, and excellent selectivity for binding to σ2 over σ1 receptors. The behavioral properties of this structural class of σ ligands have not yet been investigated. The present study evaluated 5-bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2,3-dimethoxy-benzamide, 1, a ligand shown by others to bind preferentially to σ2 over σ1 receptors, as well as dopamine D2 and D3 sites. First, we determined binding to monoamine transporters and opioid receptors, and noted 57-fold selectivity for σ2 receptors over the serotonin transporter, and >800-fold selectivity for σ2 receptors over the other sites tested. We then examined 1 in locomotor activity studies using male CD-1® mice, and saw no alteration of basal activity at doses up to 31.6 µmol/kg. Cocaine produced a fivefold increase in locomotor activity, which was attenuated by 66% upon pretreatment of mice with 1 at 31.6 µmol/kg. In vivo radioligand binding studies also were performed, and showed no occupancy of σ1 receptors or the dopamine transporter by 1, or its possible metabolites, at the 31.6 µmol/kg dose. Thus, ligand 1 profiles behaviorally as a σ2 receptor-selective antagonist that is able to counteract cocaine's motor stimulatory effects.

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“…The same authors state that the mechanism of action of EMD 57445 remains unclear because the main metabolite of EMD 57445, EMD 59 983, has substantial affinity for the dopamine D 2 and D 3 receptors [1]. In a single photon emission computed tomography (IBZM-SPECT) study, Gründer et al [10] showed a high occupancy of striatal D 2 -like dopamine receptors similar to that induced by typical neuroleptics in five schizophrenic patients treated with EMD 57445. The D 2 -occupancy rate in the striatum correlated with the plasma levels of EMD 57445 and EMD 59 983.…”

Section: Compoundmentioning

confidence: 93%

Clinical Trials with Sigma Ligands

Volz¹,

Stoll²

2004

Pharmacopsychiatry

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So far, sigma-ligands have been investigated for several indications in human studies in functional diarrhea as a model of somatoform disorder (igmesine), depression (igmesine, opipramol), anxiety (opipramol and--in animal models--siramisine), schizophrenia (panamasine, SL 82.0715, rimcazole, DuP 734, BMY 14 802), and somatoform disorders (opipramol). Results for schizophrenia failed to be clear cut and so investigations have apparently stopped for the time being. The Sigma-1-selective igmesine (200 mg) showed good results in a phase-1-model of functional diarrhea and some promising results in depressed patients. However, further development has been stopped due to marketing reasons, which is also true for siramasine, a selective sigma-2-ligand with anxiolytic properties. Opipramol, which, apart from a sigma-1- and 2-receptor liability, also possesses histamine-H(1)-antagonistic properties in connection with lower affinities for D(2) and 5-HT(2A) showed broad efficacy in generalized anxiety disorder and somatoform disorders. The receptor profile of opipramol and the results of studies of the selective sigma site ligands siramisine and igmesine suggest that opipramol acts pharmacologically and clinically via sigma receptors.

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Occupancy of striatal D 2 -like dopamine receptors after treatment with the sigma ligand EMD 57445, a putative atypical antipsychotic

Abstract: Our results suggest that a possible antipsychotic activity of EMD 57445 in schizophrenia is not necessarily attributable to its affinity for sigma receptors, but could be simply due to the potent antidopaminergic effects of EMD 59983, its main metabolite.

Cited by 20 publications

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Dopamine D2 and D3 Receptor Occupancy in Normal Humans Treated with the Antipsychotic Drug Aripiprazole (OPC 14597) A Study Using Positron Emission Tomography and [11C]Raclopride

Dopamine D2 and D3 Receptor Occupancy in Normal Humans Treated with the Antipsychotic Drug Aripiprazole (OPC 14597) A Study Using Positron Emission Tomography and [11C]Raclopride

A selective sigma‐2 receptor ligand antagonizes cocaine‐induced hyperlocomotion in mice

Clinical Trials with Sigma Ligands

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