Ex vivo binding of flibanserin to serotonin 5-HT1 Aand 5-HT2Areceptors

doi:10.1006/phrs.2000.0762

Pharmacological Research

Volume 43, Issue 2, February 2001, Pages 179-183

https://doi.org/10.1006/phrs.2000.0762 Get rights and content

Abstract

Flibanserin has been reported to be an agonist at 5-HT_1A-receptors and an antagonist at 5-HT_2Areceptors, with higher affinity for 5-HT_1Areceptors. Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects, flibanserin was shown to exert 5-HT_2Aantagonism at doses (4–5 mg kg⁻¹) that are lower or equal to those required to stimulate 5-HT_1Areceptors. In order to understand this phenomenon, the interaction of flibanserin with 5-HT_1Aand 5-HT_2Areceptors was evaluated in ex vivo binding studies. This interaction was evaluated in the prefrontal cortex, hippocampus and midbrain by using [³H]8-OH-DPAT and [³H]ketanserin to label 5-HT_1Aand 5-HT_2Areceptors, respectively. Flibanserin was given at 1, 10 and 30 mg kg⁻¹intraperitoneally. The dose of 1 mg kg⁻¹displaced both radioligands preferentially in the frontal cortex. The doses of 10 and 30 mg kg⁻¹reduced the binding of both radioligands in all the three brain regions non-selectively by about 50% and 70%, respectively. The displacement was maximal after 0.5 h and was reduced or not evident after 3 h. We conclude that 5-HT₂antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor-mediated effects.

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Cited by (11)

Ultrasound assisted one-pot synthesis and preliminary in vitro studies of salicylamide arylpiperazines as dual 5-HT<inf>1A</inf>/5-HT<inf>7</inf> ligands
2023, Journal of Molecular Structure
In our research to find new dual 5-HT_1A/5-HT₇ ligands from the long-chain arylpiperazine (LCAP) family, we applied a new synthesis method with the support of ultrasound. The first tests related to the synthesis were carried out on the preparation of approved drugs with arylpiperazine structures such as aripiprazole, trazodone and flibanserin . The results were very satisfactory. In the next stage of the research, we obtained the compounds from the LCAPs group using the sonochemical method, with salicylamide in the structure, a flexible / stiffened linker and a fragment of o-methoxyarylpiperazine / m-chloroarylpiperazine. Among the compounds obtained, two selective 5-HT_1A / 5-HT₇ ligands were selected, i.e. 2-((4-((4-(2-methoxyphenyl)piperazin-1- yl)methyl)benzyl)oxy)benzamide (18) (5-HT_1A K_i = 12.6 nM, 5-HT₇ K_i = 6.8 nM) and 2-((4-((4-(3-chlorophenyl)piperazin-1-yl)methyl)benzyl)oxy)benzamide (23) (5-HT_1A K_i = 11.6 nM, 5-HT₇ K_i = 5.5 nM).
Preclinical Abuse Potential Assessment of Flibanserin: Effects on Intracranial Self-Stimulation in Female and Male Rats
2016, Journal of Sexual Medicine
Flibanserin is a serotonin receptor subtype 1A agonist and 2A antagonist that has been approved by the Food and Drug Administration for treating female sexual interest and arousal disorder. Little is known about the abuse potential of flibanserin.
To examine abuse-related effects of flibanserin in rats using an intracranial self-stimulation (ICSS) procedure previously used to evaluate the abuse potential of other drugs.
Adult female and male Sprague-Dawley rats with electrodes implanted in the medial forebrain bundle were trained to press a lever for electrical brain stimulation under a “frequency–rate” ICSS procedure. In this procedure, increasing frequencies of brain stimulation maintain increasing rates of responding. Drugs of abuse typically increase (or “facilitate”) ICSS rates and produce leftward and upward shifts in ICSS frequency–rate curves, whereas drugs that lack abuse potential typically do not alter or only decrease ICSS rates. Initial studies determined the potency and time course of effects on ICSS produced by acute flibanserin administration (1.0, 3.2 and 10.0 mg/kg). Subsequent studies determined the effects of flibanserin (3.2–18 mg/kg) before and after a regimen of repeated flibanserin administration (5.6 mg/kg/d for 5 days). Effects of the abused stimulant amphetamine (1.0 mg/kg) were examined as a positive control.
Flibanserin effects on ICSS frequency–rate curves in female and male rats were examined and compared with the effects of amphetamine.
Baseline ICSS frequency–rate curves were similar in female and male rats. Acute and repeated administrations of flibanserin produced only decreases in ICSS rates, and rate-decreasing effects of the highest flibanserin dose (10 mg/kg) were greater in female than in male rats. In contrast to flibanserin, amphetamine produced an abuse-related increase in ICSS rates that did not differ between female and male rats.
These results suggest that flibanserin has low abuse potential. In addition, this study suggests that female rats might be more sensitive than male rats to the rate-decreasing effects of high flibanserin doses.
Multifunctional Pharmacology of Flibanserin: Possible Mechanism of Therapeutic Action in Hypoactive Sexual Desire Disorder
2011, Journal of Sexual Medicine
Citation Excerpt :
The answer appears to depend upon where these receptor subtypes are distributed in the brain, whether the excitatory or the inhibitory pathway normally prevails, and if the drug is selective for some brain regions over others. In the case of flibanserin, surprising site‐selective actions on 5‐HT1A receptors (as an agonist) and upon 5‐HT2A receptors (as an antagonist) seem to explain observations that it causes changes in monoamine neurotransmitter levels in only some brain regions, in different directions, and in different patterns over time [9,22-24,26,28]. One of the curious and still not yet fully explained observations about the actions of many psychotropic drugs is how they can apparently have regionally selective actions despite the same apparent receptor being distributed throughout many areas of the brain [33,34,42,44,49,55-59].
Flibanserin is a novel pharmacologic agent in late‐stage clinical testing for hypoactive sexual desire disorder (HSDD) in premenopausal women.
The aim of this article is to review the hypothetical mechanism of action of flibanserin in HSDD.
A literature review was conducted of all published works on flibanserin and on related studies of serotonin (5‐HT)_1A receptors and 5‐HT_2A receptors, including their actions on monoamines and on sexual function.
The main outcome measures are preclinical pharmacologic actions, especially changes in regional monoamines following treatment with flibanserin.
At clinically relevant doses, flibanserin acts predominantly at 5‐HT_1A receptors as an agonist and secondarily at 5‐HT_2A receptors as an antagonist. Additional binding actions within an order of magnitude of its 5‐HT_1A affinity, which are not likely to be clinically relevant, include weaker antagonist actions at 5‐HT_2C and 5‐HT_2B receptors, and less defined activity at dopamine (DA) D4 receptors. The 5‐HT_1A actions of flibanserin are only seen postsynaptically, which is unlike other agents such as buspirone that act at presynaptic 5‐HT_1A receptors. Furthermore, the postsynaptic actions of chronic flibanserin administration appear to demonstrate a preference for some populations of postsynaptic 5‐HT receptors, particularly those that are located on the prefrontal cortex (PFC) pyramidal neurons, which regulate monoamine release in certain selective brain regions.
The regional selectivity of flibanserin results in a unique pattern of monoamine modulation. Sustained increases in baseline of DA and norepinephrine (NE) are observed in the PFC, and flibanserin dosing increases DA and NE levels above the basal changes. Conversely, flibanserin induces transient decreases in 5‐HT levels in some brain areas such as the PFC, nucleus accumbens, and hypothalamus, but not in other brain areas such as the hippocampus. Therefore, since DA and NE are excitatory and 5‐HT is inhibitory to sexual desire and arousal, it is tempting to postulate that the actions of flibanserin on serotonin receptors at the PFC pyramidal neurons, resulting in increased DA and NE yet reduced 5‐HT in the PFC, are the mechanistic underpinnings of enhancing sexual desire in HSDD. Stahl SM, Sommer B, and Allers KA. Multifunctional pharmacology of flibanserin: Possible mechanism of therapeutic action in hypoactive sexual desire disorder. J Sex Med 2011;8:15–27.
Phenotype prediction of deleterious nonsynonymous single nucleotide polymorphisms in human alcohol metabolism-related genes: A bioinformatics study
2010, Alcohol
Nonsynonymous single nucleotide polymorphisms (nsSNPs) are thought as potential disease modifiers because they alter the encoded amino acid sequence and are likely to affect the function of the proteins accounting for susceptibility to disease. Distinguishing the functionally significant nsSNPs from tolerant nsSNPs is helpful to characterize the genetic basis of human diseases and assess individual susceptibility to diseases. Many nsSNPs have been found in alcohol metabolism-related genes but there is poor knowledge on the relationship between the genotype and phenotype of nsSNPs in these genes. In this study, we have identified a total of 203 nsSNPs in 29 human alcohol metabolism-related genes from the National Center for Biotechnology Information (NCBI) dbSNP and SWISS-Prot databases. Using the PolyPhen and SIFT algorithms, 43% of nsSNPs in alcohol metabolism-related genes were predicted to have functional impacts on protein function with a significant concordance of the prediction results between the two algorithms. The prediction accuracy is about 77–81% of all the nsSNPs based on the results of in vivo and in vitro studies. These amino acid substitutions are supposed to be the pathogenetic basis for the alteration of metabolism enzyme activity and the association with disease susceptivity. The phenotype of nsSNPs predicted as deleterious needs to be clarified in further studies and the prediction of nsSNPs in human alcohol metabolism-related genes would be useful hints for further genotype–phenotype studies on the individual difference in susceptivity to alcohol-related diseases.
Acute and repeated flibanserin administration in female rats modulates monoamines differentially across brain areas: A microdialysis study
2010, Journal of Sexual Medicine
Citation Excerpt :
This is consistent with the previous study demonstrating decreased 5-HT in the DRN and mPFC but not in the hippocampus following flibanserin treatment [14]. It is possible that the inhibitory effect of flibanserin on 5-HT neurotransmission is explained by the 5-HT1A agonistic property of this drug [7,14,20]. Activation of the 5-HT1A autoreceptors of DRN inhibits the firing activity of 5-HT neurons, resulting in a decrease in extracellular 5-HT in terminal regions [21–23].
Hypoactive sexual desire disorder (HSDD) is defined as persistent lack of sexual fantasies or desire marked by distress. With a prevalence of 10% it is the most common form of female sexual dysfunction. Recently, the serotonin-1A (5-HT_1A) receptor agonist and the serotonin-2A (5-HT_2A) receptor antagonist flibanserin were shown to be safe and efficacious in premenopausal women suffering from HSDD in phase III clinical trials.
The current study aims to assess the effect of flibanserin on neurotransmitters serotonin (5-HT), norepinephrine (NE), dopamine (DA), glutamate, and γ-aminobutyric acid (GABA) in brain areas associated with sexual behavior.
Flibanserin was administered to female Wistar rats (280–350 g). Microdialysis probes were stereotactically inserted into the mPFC, NAC, or MPOA, under isoflurane anesthesia. The extracellular levels of neurotransmitters were assessed in freely moving animals, 24 hours after the surgery.
Dialysate levels of DA, NE, and serotonin from medial prefrontal cortex (mPFC), nucleus accumbens (NAC), and hypothalamic medial preoptic area (MPOA) from female rats.
Acute flibanserin administration decreased 5-HT and increased NE levels in all tested areas. DA was increased in mPFC and MPOA, but not in the NAC. Basal levels of NE in mPFC and NAC and of DA in mPFC were increased upon repeated flibanserin administration, when compared to vehicle-treated animals. The basal levels of 5-HT were not altered by repeated flibanserin administration, but basal DA and NE levels were increased in the mPFC. Glutamate and GABA levels remained unchanged following either repeated or acute flibanserin treatment.
Systemic administration of flibanserin to female rats differentially affects the monoamine systems of the brain. This may be the mechanistic underpinning of flibanserin's therapeutic efficacy in HSDD, as sexual behavior is controlled by an intricate interplay between stimulatory (catecholaminergic) and inhibitory (serotonergic) systems. Allers KA, Dremencov E, Ceci A, Flik G, Ferger B, Cremers TIFH, Ittrich C, and Sommer B. Acute and repeated flibanserin administration in female rats modulates monoamines differentially across brain areas: A microdialysis study.
Mechanism of action of flibanserin in the learned helplessness paradigm in rats
2001, European Journal of Pharmacology
The mechanism of action of flibanserin, a 5-HT_1A receptor agonist and a 5-HT_2A receptor antagonist, was investigated in learned helplessness in rats. The effect of flibanserin (32 mg/kg, i.p. 30 min before testing) on learned helplessness was not antagonized by the (a) 5-HT synthesis inhibitor parachlorophenylalanine (pCPA; 150 mg/kg p.o.×3 times), which reduced brain 5-HT by 89%; (b) 5-HT_1A receptor antagonists (±)-N-tert-butyl-3-4-(2-ethoxyphenyl)piperazin-1yl-2-phenyl propionamide [WAY100135; 10 mg/kg, i.p. 30 min before flibanserin, or 40 mg/kg, s.c. 15 min before flibanserin] and tertatolol (2.5 and 5 mg/kg, i.p. 30 min before flibanserin); and (c) 5-HT₂ receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI; 3 mg/kg, s.c. simultaneously with flibanserin). The effect of flibanserin on learned helplessness was antagonized by the dopamine D₁ receptor antagonist [R]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390; 0.1 mg/kg, i.p. 30 min before flibanserin) and by the opioid receptor antagonist naloxone (3 mg/kg, s.c. 15 min before flibanserin). Flibanserin (32 and 64 mg/kg) did not induce conditioned place preference. In conclusion, flibanserin improved rats' performance in the learned helplessness paradigm, by stimulating dopamine D1 and opioid receptors, probably indirectly, since flibanserin has a low affinity for these receptors.

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¹: Corresponding author. Boehringer Ingelheim Pharma KG, CNS Department, Building J63, Birkendorfer Strasse 65, 88397 Biberach an der Riss, Germany. Email: [email protected]

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Pharmacological Research

Abstract

References (17)

Does functional relationship exist between 5-HT_1Aand 5-HT₂receptors?

Pharmacol Biochem Behav

Flibanserin

Drugs of the Future

In vivo electrophysiological assessment of the agonistic properties of flibanserin at pre- and postsynaptic 5-HT_1Areceptors in the rat brain

Synapse

Receptor reserve for 5-hydroxytryptamine_1A-mediated inhibition of serotonin synthesis: possible relationship to anxiolytic properties of 5-hydroxytryptamine_1Aagonists

Mol Pharmacol

Lack of apparent receptor reserve at postsynaptic 5-hydroxytryptamine_1Areceptors negatively coupled to adenylyl cyclase activity in rat hippocampal membranes

Mol Pharmacol

Effects of intermittent and continuous subchronic administration of raclopride on motor activity, dopamine turnover and receptor occupancy in the rat

Pharmacol Toxicol

The D₂dopamine receptor occupancy of risperidone and its relationship to extrapyramidal symptoms: a PET study

Life Sci

The effect of BIMT 17, a new potential antidepressant, in the forced swimming test in mice

Behav Pharmacol

Cited by (11)

Ultrasound assisted one-pot synthesis and preliminary in vitro studies of salicylamide arylpiperazines as dual 5-HT<inf>1A</inf>/5-HT<inf>7</inf> ligands

Preclinical Abuse Potential Assessment of Flibanserin: Effects on Intracranial Self-Stimulation in Female and Male Rats

Multifunctional Pharmacology of Flibanserin: Possible Mechanism of Therapeutic Action in Hypoactive Sexual Desire Disorder

Phenotype prediction of deleterious nonsynonymous single nucleotide polymorphisms in human alcohol metabolism-related genes: A bioinformatics study

Acute and repeated flibanserin administration in female rats modulates monoamines differentially across brain areas: A microdialysis study

Mechanism of action of flibanserin in the learned helplessness paradigm in rats

Regular ArticleEx vivo binding of flibanserin to serotonin 5-HT1 Aand 5-HT2Areceptors

Abstract

Pharmacol Biochem Behav

Flibanserin

Drugs of the Future

In vivo electrophysiological assessment of the agonistic properties of flibanserin at pre- and postsynaptic 5-HT1Areceptors in the rat brain

Synapse

Receptor reserve for 5-hydroxytryptamine1A-mediated inhibition of serotonin synthesis: possible relationship to anxiolytic properties of 5-hydroxytryptamine1Aagonists

Mol Pharmacol

Lack of apparent receptor reserve at postsynaptic 5-hydroxytryptamine1Areceptors negatively coupled to adenylyl cyclase activity in rat hippocampal membranes

Mol Pharmacol

Effects of intermittent and continuous subchronic administration of raclopride on motor activity, dopamine turnover and receptor occupancy in the rat

Pharmacol Toxicol

The D2dopamine receptor occupancy of risperidone and its relationship to extrapyramidal symptoms: a PET study

Life Sci

The effect of BIMT 17, a new potential antidepressant, in the forced swimming test in mice

Behav Pharmacol

Regular Article
Ex vivo binding of flibanserin to serotonin 5-HT_{1 A}and 5-HT_2Areceptors

In vivo electrophysiological assessment of the agonistic properties of flibanserin at pre- and postsynaptic 5-HT_1Areceptors in the rat brain

Receptor reserve for 5-hydroxytryptamine_1A-mediated inhibition of serotonin synthesis: possible relationship to anxiolytic properties of 5-hydroxytryptamine_1Aagonists

Lack of apparent receptor reserve at postsynaptic 5-hydroxytryptamine_1Areceptors negatively coupled to adenylyl cyclase activity in rat hippocampal membranes

The D₂dopamine receptor occupancy of risperidone and its relationship to extrapyramidal symptoms: a PET study