Binding of typical and atypical antipsychotics to 5-HT1C and 5-HT2 sites: clozapine potently interacts with 5-HT1C sites

doi:10.1016/0014-2999(90)94100-C

European Journal of Pharmacology

Volume 191, Issue 1, 20 November 1990, Pages 93-96

https://doi.org/10.1016/0014-2999(90)94100-C Get rights and content

Abstract

We determined the affinity of several typical and atypical antipsychotics for the 5-HT_1C and 5-HT₂ sites using radioligand binding assays. Most of the antipsychotics tested appeared to bind to 5-HT₂ sites with affinities that were fairly high (i.e. pK_i values between 7 and 9) and significantly higher than for 5-HT_1C sites. In contrast, clozapine was found to have a significantly higher affinity for 5-HT_1C than for 5-HT₂ sites. Clozapine had the highest affinity for 5-HT_1C sites of all the compounds tested. These findings are consistent with the hypothesis that an interaction with 5-HT₂ receptors may be relevant to the clinical activity of typical antipsychotics. The findings also suggest, however, that an interaction with 5-HT_1C sites may be relevant to the mechanism of clinical action of clozapine and, perhaps, of other atypical antipsychotics.

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In addition, fluoxetine, citalopram and SSRIs, also act as 5-HT2CR antagonists (Ni and Miledi, 1997; Palvimaki et al., 1996). Some atypical and typical antipsychotic agents such as clozapine, loxapine, and chlorpromazine have a relatively high affinity for 5-HT2C binding sites (Canton et al., 1990; Jenck et al., 1993; Roth et al., 1992). Some studies in Flinder sensitive line (FSL) rats (a putative animal model of depression) suggest a hyperfunctionality of 5-HT2CRs that could be related to decreased DA levels in the NAc.
5-HT2Rs have a different genomic organization from other 5-HT2Rs. 5HT2CR undergoes post-transcriptional pre-mRNA editing generating diversity among RNA transcripts. Selective post-transcriptional editing could be involved in the pathophysiology of psychiatric disorders through impairment in G-protein interactions. Moreover, it may influence the therapeutic response to agents such as atypical antipsychotic drugs. Additionally, 5-HT2CR exhibits alternative splicing.
Central serotonergic and dopaminergic systems interact to modulate normal and abnormal behaviors. Thus, 5HT2CR plays a crucial role in psychiatric disorders. 5HT2CR could be a relevant pharmacological target in the treatment of neuropsychiatric disorders. The development of drugs that specifically target 5-HT2C receptors will allow for better understanding of their involvement in the pathophysiology of psychiatric disorders including schizophrenia, anxiety, and depression.
Among therapeutic means currently available, most drugs used to treat highly morbid psychiatric diseases interact at least partly with 5-HT2CRs. Pharmacologically, 5HT2CRs, have the ability to generate differentially distinct response signal transduction pathways depending on the type of 5HT2CR agonist. Although this receptor property has been clearly demonstrated, in vitro, the eventual beneficial impact of this property opens new perspectives in the development of agonists that could activate signal transduction pathways leading to better therapeutic efficiency with fewer adverse effects.
New therapeutic opportunities for 5-HT<inf>2C</inf> receptor ligands in neuropsychiatric disorders
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The 5-HT_2C receptor (R) displays a widespread distribution in the CNS and is involved in the action of 5-HT in all brain areas. Knowledge of its functional role in the CNS pathophysiology has been impaired for many years due to the lack of drugs capable of discriminating among 5-HT₂R subtypes, and to a lesser extent to the 5-HT_1B, 5-HT₅, 5-HT₆ and 5-HT₇Rs. The situation has changed since the mid-90s due to the increased availability of new and selective synthesized compounds, the creation of 5-HT_2C knock out mice, and the progress made in molecular biology. Many pharmacological classes of drugs including antipsychotics, antidepressants and anxiolytics display affinities toward 5-HT_2CRs and new 5-HT_2C ligands have been developed for various neuropsychiatric disorders. The 5-HT_2CR is presumed to mediate tonic/constitutive and phasic controls on the activity of different central neurobiological networks. Preclinical data illustrate this complexity to a point that pharmaceutical companies developed either agonists or antagonists for the same disease.
In order to better comprehend this complexity, this review will briefly describe the molecular pharmacology of 5-HT_2CRs, as well as their cellular impacts in general, before addressing its central distribution in the mammalian brain. Thereafter, we review the preclinical efficacy of 5-HT_2C ligands in numerous behavioral tests modeling human diseases, highlighting the multiple and competing actions of the 5-HT_2CRs in neurobiological networks and monoaminergic systems. Notably, we will focus this evidence in the context of the physiopathology of psychiatric and neurological disorders including Parkinson's disease, levodopa-induced dyskinesia, and epilepsy.
Antitumor activity of histamine and clozapine in a mouse experimental model of human melanoma
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In SK-N-MC/hH4, CLZ binds with moderate potency to the hH4R and exerts full agonistic activity at the hH4R. The antipsychotic effects are thought to be mediated principally by 5-HT2A/2C and dopamine receptor blockade [32,33]. As it is well known, neurons (i.e. dopaminergic) and melanocytes share the same ectodermal origin and are both able to produce melanin.
Functional presence of histamine H₄ receptor (H₄R) was demonstrated in human melanoma cell lines and biopsies.
The purposes of this work were to investigate signal transduction pathways and biological responses triggered by the activation of H₄R in human primary (WM35) and metastatic (M1/15) melanoma cell lines and to evaluate the in vivo antitumor activity of histamine (HA) and clozapine (CLZ) on human M1/15 melanoma xenografts.
Clonogenic assay, incorporation of BrdU, cell cycle distribution, phosphorylation levels of ERK1/2 and cAMP production were evaluated in vitro. An experimental human melanoma model was developed into athymic nude mice. Tumor growth, survival and histochemical studies were performed in order to investigate the expression levels of H₄R, HA, PCNA, mitotic index (MI), and angiogenesis.
The results indicate that H₄R agonists inhibited forskolin-induced cAMP levels only in M1/15 cells while increased phosphorylation levels of ERK1/2 and decreased proliferation in both cell types. In vivo studies show that HA and CLZ (1 mg kg⁻¹, sc) significantly increased median survival and decreased tumor volume. These effects were associated to a reduction in MI, in the expression of proliferation marker and in intratumoral neovascularization.
We conclude that HA and CLZ exhibit an antitumoral effect in vitro and in vivo on human melanoma, suggesting the therapeutic potential of these compounds for the treatment of malignant melanoma.
Serotonin modulation of the basal ganglia circuitry: therapeutic implication for Parkinson's disease and other motor disorders
2008, Progress in Brain Research
Citation Excerpt :
This was suggested by early clinical studies indicating that the 5-HT2A/2C receptor antagonist ritanserin (Leysen et al., 1985; Bersani et al., 1990) can ameliorate negative symptoms as well as attenuate exciting EPS in schizophrenics treated with classical APDs (Bersani et al., 1990; Miller et al., 1990). The relevance of 5-HT2C receptor blocking in the effect of atypical APDs was shown by Canton et al. (1990), who revealed the high affinity of clozapine and risperidone for 5-HT2C sites in the rat choroid plexus. These findings were subsequently confirmed (Kuoppamaki et al., 1993, 1995; Schotte et al., 1993; Canton et al., 1994) and extended to brain sections (Roth et al., 1992, 1998).
Several recent studies have emphasized a crucial role for the interactions between serotonergic and dopaminergic systems in movement control and the pathophysiology of basal ganglia. These observations are supported by anatomical evidence demonstrating large serotonergic innervation of all the basal ganglia nuclei. In fact, serotonergic terminals have been reported to make synaptic contacts with both substantia nigra dopamine-containing neurons and their terminal areas such as the striatum, the globus pallidus and the subthalamus. These brain areas contain a high concentration of serotonin (5-HT), with the substantia nigra pars reticulata receiving the greatest input. In this chapter, the distribution of different 5-HT receptor subtypes in the basal ganglia nuclei will be described. Furthermore, evidence demonstrating the serotonergic control of basal ganglia activity will be reviewed and the contribution of the different 5-HT receptor subtypes examined. The new avenues that the increasing knowledge of 5-HT in motor control has opened for exploring the pathophysiology and pharmacology of Parkinson's disease and other movement disorders will be discussed. It is clear that these avenues will be fruitful, despite the disappointing results so far obtained by clinical studies with selective 5-HT ligands. Nevertheless, these studies have led to a great increase in the attention given to the neurotransmitters of the basal ganglia and their connections.
6 5-HT<inf>2C</inf> Ligands: Recent Progress
2008, Progress in Medicinal Chemistry
Citation Excerpt :
Typical antipsychotics have relatively low affinities for the 5-HT2C receptor. However, subsequent studies suggested that atypicality correlated better with high affinity for the 5-HT2A receptor, as many atypical antipsychotic agents such as risperidone or quetiapine were found to have high affinity for the 5-HT2A receptor, but relatively low affinity for the 5-HT2C site in binding studies [118, 119]. Nevertheless, evidence that the selective 5-HT2C receptor antagonist SB-242084 (14) increases dopamine release in the rat prefrontal cortex [90, 120], suggests that 5-HT2C receptor antagonism may contribute to the preferential effect of atypical antipsychotic agents on prefrontal cortical dopaminergic (DA) function and hence ameliorate both EPS and negative symptoms.
Serotonin (5-hydroxytryptamine, 5-HT) was characterized as a factor released by blood platelets during clotting that causes vasoconstriction. Immunochemical and histochemical techniques establish that 5-HT is an important and widely distributed central neurotransmitter. 5-HT is largely distributed within neurons that project from 9 clusters of cell bodies mostly located in the midbrain and hindbrain. The chapter describes the 5-HT receptors and the 5-HT₂ receptor family. The principle therapeutic targets for the development of 5-HT_2C receptor agonists is the treatment of obesity, anxiety, schizophrenia, depression, Parkinson's Disease, drugs of abuse, and epilepsy. No profound side-effects are reported that might complicate the development of 5-HT_2C receptor antagonists. The chapter describes the chemical explorations around ligands for 5-HT_2C that include agonists, antagonists and inverse agonists. Considerable work has also targeted 5-HT_2c receptor antagonism as part of a mixed pharmacology. The main breakthroughs appear to be in the design of compounds that have robust selectivity across the 5-HT₂ family of receptors. Thus, progress with these compounds may determine the degree of future interest in this target class.
Alterations of Serotonin Transmission in Schizophrenia
2007, International Review of Neurobiology
Citation Excerpt :
More recently, the demonstration of the superior efficacy of clozapine for treatment of schizophrenia and of its low incidence of EPS has promoted a renewed interest in the role of 5‐HT2 antagonism in schizophrenia. Given the lack of pharmacological specificity of clozapine, many theories have been proposed to account for its particular clinical profile and have been extensively reviewed elsewhere (Canton et al., 1990; Deutch et al., 1991; Lieberman, 1993; Meltzer, 1991; Seeman, 1992). Most prominent hypotheses include a higher in vivo selectivity of clozapine as compared to typical neuroleptics for (1) “corticolimbic” D2 receptors, as compared to “striatal” D2 receptors (Altar et al., 1986; Deutch et al., 1992), possibly as an effect of lower competition with endogenous DA in corticolimbic regions than in striatal regions (Seeman, 1990); (2) D4 receptors (Seeman, 1992; Van Tol et al., 1991); (3) 5‐HT2 receptors (Altar et al., 1986; Meltzer, 1989; Meltzer et al., 1989; Rasmussen and Aghajanian, 1988).
A role for serotonin alterations in the pathophysiology of schizophrenia has long been suspected because of the psychotogenic effects of serotonergic agonists and the therapeutic effects of 5‐HT₂ antagonism. This chapter is a review of the evidence derived from pharmacological studies, postmortem, and imaging studies that have assessed the role of serotonin transmission in schizophrenia. While a clear picture of specific serotonergic alterations in schizophrenia has not emerged despite much research, this review reinforces a modulatory role of serotonergic agents on dopamine transmission in schizophrenia, which may contribute to the therapeutic effects of atypical antipsychotics.

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Short communicationBinding of typical and atypical antipsychotics to 5-HT1C and 5-HT2 sites: clozapine potently interacts with 5-HT1C sites

Abstract

Pharmacol. Biochem. Behav.

Trends Pharmacol. Sci.

Life Sci.

European. J. Pharmacol.

Interaction of psychotropic drugs with central 5-HT3 recognition sites: fact or artifact?

European J. Pharmacol.

Short communication
Binding of typical and atypical antipsychotics to 5-HT_1C and 5-HT₂ sites: clozapine potently interacts with 5-HT_1C sites

Interaction of psychotropic drugs with central 5-HT₃ recognition sites: fact or artifact?