Deramciclane, a putative anxiolytic drug, is a serotonin 5-HT2C receptor inverse agonist but fails to induce 5-HT2C receptor down-regulation

  title={Deramciclane, a putative anxiolytic drug, is a serotonin 5-HT2C receptor inverse agonist but fails to induce 5-HT2C receptor down-regulation},
  author={E. -P. P{\"a}lvim{\"a}ki and Hannu Majasuo and Mikko Kuoppam{\"a}ki and Pekka T. Männistö and E. K. G. Syv{\"a}lahti and Jarmo Hietala},
Abstract Deramciclane (EGIS-3886) is a novel anxiolytic agent that binds with high affinity to 5-HT2A/2C receptors. The interactions of deramciclane with the serotonin 5-HT2C receptor were characterized further using receptor phosphoinositide hydrolysis assays and receptor autoradiography. Deramciclane antagonized 5-HT2C receptor mediated 5-HT-stimulated phosphoinositide hydrolysis with an IC50 value of 168 nM. Deramciclane also decreased basal phosphoinositide hydrolysis by up to 33% (EC50… 

Sertindole is a serotonin 5-HT2c inverse agonist and decreases agonist but not antagonist binding to 5-HT2c receptors after chronic treatment

The preferential downregulation of 5-HT2C receptor agonist (G-protein-coupled) sites by chronic administration seemed to differentiate sertindole from clozapine at these dose regimens, suggesting that the 5- HT2c receptor downregulation during repeated dosing may contribute to therapeutic efficacy and/or side effects of sERTindole treatment.

Brain 5-HT2A receptor occupancy of deramciclane in humans after a single oral administration – a positron emission tomography study

Deramciclane penetrates the blood-brain barrier in humans and binds to the 5-HT2A receptors in the frontal cortex in a saturable manner in vivo, indicating a non-5- HT2A receptor binding component of this radioligand in frontal cortex.

Comparison of the effects of deramciclane, ritanserin and buspirone on extracellular dopamine and its metabolites in striatum and nucleus accumbens of freely moving rats.

There is at least a 5-fold margin between the anxiolytic and neuroleptic doses of deramciclane in the rat, particularly in mesolimbic regions.

Differential effects of fluoxetine and citalopram treatments on serotonin 5-HT(2C) receptor occupancy in rat brain.

Ex vivo receptor occupancy measurements provide evidence that direct occupancy of 5-HT(2C) receptors may contribute to the mechanism of action of fluoxetine, and demonstrate pharmacodynamic differences between fluoxettine and citalopram at the level of5-HT-2C receptors.

Effect of the novel anxiolytic drug deramciclane on cytochrome P450 2D6 activity as measured by desipramine pharmacokinetics

Although deramciclane seems to be a weaker inhibitor of CYP2D6 than paroxetine, dose adjustment of drugs metabolized by CYP 2D6 may be needed when used concomitantly with deram ciclane.

Isoteoline, a putative serotonin antagonist, inhibits meta -chlorophenylpiperazine, but not 1-(2, -dimethoxy-4-iodphenyl)-2-aminopropane and 8-hydroxy-2-(di-n-propylamino)-tetraline-induced increase of serum prolactin levels.

It is concluded that the inhibition of the m CPP-induced rise of PRL levels by IST confirmed the serotonin antagonistic activity, previously demonstrated for this compound in other studies.

The role of 5-HT2C receptors in affective disorders.

Results are consistent with an important hypothesis proposing that 5-HT has a complex, dual action on the neural mechanism of anxiety by either facilitating or inhibiting different kinds of anxiety in different brain regions and suggest that5-HT(2C) receptor subtypes play an important role in the therapeutic properties of SSRIs.

Effect of the novel anxiolytic drug deramciclane on the pharmacokinetics and pharmacodynamics of the CYP3A4 probe drug buspirone

Deramciclane does not inhibit CYP3A4 activity as measured by buspirone pharmacokinetics, and there were no indications of relevant pharmacodynamic interaction after multiple doses of deramcIClane and a single dose of buspir one.

Inverse agonist activity of atypical antipsychotic drugs at human 5-hydroxytryptamine2C receptors.

The data suggest that 5-HT(2C) inverse agonist activity is associated with atypical antipsychotic drugs with moderate to high affinity for 5- HT( 2C) receptors, and imply that effects of atypICAL antipsychotics drugs on the 5-ht(2 C) receptor may play a role in their unique clinical properties.

Receptor binding profile and anxiolytic‐type activity of deramciclane (EGIS‐3886) in animal models

The present series of experiments was done to characterize the properties of deramciclane, a new antiserotonergic drug, in both receptor binding studies in vitro and in a number of anxiolytic,



Serotonergic antagonists differentially inhibit spontaneous activity and decrease ligand binding capacity of the rat 5-hydroxytryptamine type 2C receptor in Sf9 cells.

The relative abilities of antagonists to produce loss of binding showed a good correlation with their reported abilities to down-regulate 5-HT2 receptors in vivo after chronic treatment, suggesting that these actions reflect the same underlying process.

Regulation of 5-HT2 receptors in rat cortex. Studies with a putative selective agonist and an antagonist.

Data indicate that in chronic treatment, DOI, like ketanserin, is highly selective for 5-HT2 vs5-HT1 sites at behaviorally useful doses.

5-HT1C receptor-mediated phosphoinositide hydrolysis in the rat choroid plexus after chronic treatment with clozapine.

Repeated administration of SR 46349B, a selective 5-hydroxytryptamine2 antagonist, up-regulates 5-hydroxytryptamine2 receptors in mouse brain.

It is suggested for the first time that an up-regulation of 5-HT2 receptors can occur after repeated treatment with a selective 5- HT2 receptor antagonist.

Behavioral studies with anxiolytic drugs. VI. Effects on punished responding of drugs interacting with serotonin receptor subtypes.

Behavioral and neurochemical data indicate that the effects of these drugs on other neurotransmitter systems do not play a significant role in their anxiolytic actions, and suggestions that decreased 5-HT neurotransmission is involved in the results of novel nonbenzodiazepine anxIOlytics such as buspirone are consistent.

Regulation of 5-HT2 and 5-HT1C serotonin receptor levels. Methodology and mechanisms.

  • B. RothM. HamblinR. Ciaranello
  • Biology, Psychology
    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
  • 1990
Preliminary information suggests that developmentally induced alterations in 5-HT2 and5-HT1c receptors may be due to transcriptional regulation while changes caused by mianserin treatment might bedue to posttranslational processes.

Recent developments in 5HT-related pharmacology of animal models of anxiety

  • C. Gardner
  • Biology, Psychology
    Pharmacology Biochemistry and Behavior
  • 1986

Putative selective 5-HT-2 antagonists block serotonin 5-HT-1c receptors in the choroid plexus.

Functional studies of 5-HT-stimulated phosphoinositide hydrolysis showed that ritanserin blocks the effect of5-HT and that it functions as a competitive antagonist of the 5- HT-1c receptor in intact choroid plexus.