Functional Selectivity and Antidepressant Activity of Serotonin 1A Receptor Ligands (original) (raw)
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European Journal of Pharmacology, 1993
A variety of antidepressants of different chemical classes were tested for their in vivo and in vitro activity at 5-HTlc receptors in the brain. Conventional tricyclic antidepressants (imipramine, desipramine, maprotiline, clomipramine, trimipramine, amitriptyline, nortriptyline, doxepin, amoxapine) as well as mianserin and trazodone were found to display high to low nanomolar affinity for 5-HTlc receptors. Antidepressants of other chemical classes and with other mechanisms of action (affecting amine uptake systems: fluoxetine, citalopram, sertraline, fluvoxamine, nomifensine, amineptine; or monoamine oxidase inhibitors: moclobemide, iproniazid) had negligible affinities (micromolar range) for 5-HTlc receptors, except fluoxetine. When tested in an in vivo rat model thought to reveal functional agonistic or antagonistic properties at 5-HTlc receptors, all antidepressants displaying high affinity for this receptor type (except clomipramine and trimipramine)
Antidepressants are functional antagonists at the serotonin type 3 (5-HT3) receptor
Molecular Psychiatry, 2003
Antidepressants are commonly supposed to enhance serotonergic and/or noradrenergic neurotransmission by inhibition of neurotransmitter reuptake through binding to the respective neurotransmitter transporters or through inhibition of the monoamine oxidase. Using the concentration-clamp technique and measurements of intracellular Ca 2 þ , we demonstrate that different classes of antidepressants act as functional antagonists at the human 5-HT 3A receptor stably expressed in HEK 293 cells and at endogenous 5-HT 3 receptors of rat hippocampal neurons and N1E-115 neuroblastoma cells. The tricyclic antidepressants desipramine, imipramine, and trimipramine, the serotonin reuptake inhibitor fluoxetine, the norepinephrine reuptake inhibitor reboxetine, and the noradrenergic and specific serotonergic antidepressant mirtazapine effectively reduced the serotonin-induced Na þ -and Ca 2 þ -currents in a dose-dependent fashion. This effect was voltage-independent and, with the exception of mirtazapine, noncompetitive. Desipramine, imipramine, trimipramine, and fluoxetine also accelerated receptor desensitization. Moclobemide and carbamazepine had no effect on the serotonin-induced cation current. By analyzing analogues of desipramine and carbamazepine, we found that a basic propylamine side chain increases the antagonistic potency of tricyclic compounds, whereas it is abolished by an uncharged carboxamide group. The antagonistic effects of antidepressants at the 5-HT 3 receptor did not correlate with their effects on membrane fluidity. In conclusion, structurally different types of antidepressants modulate the function of this ligand-gated ion channel. This may represent a yet unrecognized pharmacological principle of antidepressants.
Serotonin4 (5-HT4) Receptor Agonists Are Putative Antidepressants with a Rapid Onset of Action
Neuron, 2007
Current antidepressants are clinically effective only after several weeks of administration. Here, we show that serotonin 4 (5-HT 4 ) agonists reduce immobility in the forced swimming test, displaying an antidepressant potential. Moreover, a 3 day regimen with such compounds modifies rat brain parameters considered to be key markers of antidepressant action, but that are observed only after 2-3 week treatments with classical molecules: desensitization of 5-HT 1A autoreceptors, increased tonus on hippocampal postsynaptic 5-HT 1A receptors, and enhanced phosphorylation of the CREB protein and neurogenesis in the hippocampus. In contrast, a 3 day treatment with the SSRI citalopram remains devoid of any effect on these parameters. Finally, a 3 day regimen with the 5-HT 4 agonist RS 67333 was sufficient to reduce both the hyperlocomotion induced by olfactory bulbectomy and the diminution of sucrose intake consecutive to a chronic mild stress. These findings point out 5-HT 4 receptor agonists as a putative class of antidepressants with a rapid onset of action.
The International Journal of Neuropsychopharmacology, 2010
F15599 is a novel agonist with high selectivity and efficacy at serotonin 5-HT 1A receptors (5-HT 1A Rs). In signal transduction, electrophysiological and neurochemical tests, F15599 preferentially activates postsynaptic 5-HT 1A Rs in rat frontal cortex. Such a profile may translate to an improved profile of therapeutic activity for mood disorders. The in-vivo effects of F15599 were therefore compared with those of a related compound, F13714, in rat models of antidepressant activity and 5-HT 1A R activation : forced swimming test (FST), conditioned stress-induced ultrasonic vocalization, 5-HT syndrome, plasma corticosterone and body temperature. Acute administration of F15599 or F13714 reduced immobility in the FST at low doses ; these effects were long lasting and the effects of F15599 were maintained after repeated (5 d, p.o.) administration. Both compounds decreased ultrasonic vocalization duration at low doses. In contrast, higher doses of F15599 were required to induce lower lip retraction, elements of the 5-HT behavioural syndrome, hypothermia and to increase plasma corticosterone levels. Notably, there was a greater separation of ED 50 between FST and other effects for F15599 than for F13714. Thus, the in-vivo potency of F15599 in models of antidepressant/anti-stress activity is similar to that of F13714, despite the fact that the latter has an in-vitro potency two orders of magnitude greater. In contrast F15599 has a lower propensity than F13714 to induce other serotonergic signs. The distinctive pharmacological profile of F15599 suggests that preferential targeting of post-synaptic 5-HT 1A Rs constitutes a promising strategy for improved antidepressant therapy.
In vitro profile of the antidepressant candidate OPC14523 at rat and human 5HT 1A receptors
European Journal of Pharmacology, 2005
This study determined the in vitro functional profile of 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2quinolinone monomethanesulfonate (OPC-14523) at rat and human serotonin (5-HT) 5-HT 1A receptors and binding affinity of OPC-14523 at human frontocortical 5-HT 1A receptors. OPC-14523 (1 AM) increased guanosine-5V-O-(3-[ 35 S]thio)-triphosphate ([ 35 S]GTPgS) binding to 5-HT 1A receptor-containing regions of rat brain tissue sections (¨53% of the effect of 1 AM (+)8-hydroxy-2-(di-n-propylamino)tetralin ((+)8-OH-DPAT) that were blocked by the selective 5-HT 1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2pyridinylcyclohexanecarboxamide (WAY-100635). OPC-14523 also behaved as a partial agonist in its stimulation of [ 35 S]GTPgS binding to membranes from rat hippocampus (pEC 50 = 7.60 T 0.23, E max = 41.1% of the effect of 10 AM (+)8-OH-DPAT), human frontal cortex (pEC 50 = 7.89 T 0.08; E max = 64% of the effect of 10 AM (+)8-OH-DPAT), and Chinese Hamster Ovary cells expressing cloned human 5-HT 1A receptors (pEC 50 = 8.0 T 0.11; E max = 85.5% of the effect of 10 AM 5-HT), and all of these effects of OPC-14523 were blocked by WAY-100635.
Journal of psychiatry & neuroscience : JPN, 2008
We sought to demonstrate whether the specific activation of serotonin1B (5-HT1B) heteroreceptors by systemic or local administration of the selective 5-HT1B receptor agonist anpirtoline could mediate antidepressant-like effects in mice. We confirmed the selectivity of action of anpirtoline in the forced swim test (FST) in 5-HT1B knockout mice. We then evaluated the behavioural effects of anpirtoline on 5-HT-lesioned (5,7-dihydroxytryptamine creatinine [5,7-DHT]) and 5-HT-depleted (p-CPA) mice. We estimated the depletion level and selectivity of action of 5,7-DHT and p-CPA by measuring the neurotransmitter levels and [3H]-citalopram binding. We investigated the antidepressant-like effect of anpirtoline when locally perfused in an area of the brain where the response is mainly attributable to presynaptic (cortex and hippocampus) or postsynaptic receptors (substantia nigra and caudate putamen). Furthermore, we evaluated the effect of the 5-HT1B receptor antagonist GR127935 on the activ...
Pharmacodynamics of Serotonin. Emphasis on 5HT-3 Antagonists and SSRI Medication (II)
2016
This paper presents a literature review of the pharmacology of serotonin. It focuses on the metabolism and transport of serotonin and on 5-HT receptors and their clinical signifi cance. This report highlights the substances that affect serotonin signalling and body levels and may be employed in treating various disorders: either directly, by influencing the serotonin receptors or, indirectly, by inhibiting serotonin reuptake. The review will be published in two separate parts. The fi rst part will contain a short introduction in the pharmacology of serotonin and it will emphasize the pharmacological properties of the fi rst three of the 5-HT receptors (5-HT1, 5-HT2, 5-HT3). In the second part, the other four types of 5-HT receptors (5-HT4, 5-HT5, 5-HT6, 5-HT7) will be presented along with tendencies and prospects in influencing serotonin transporter (SERT) through selective serotonin reuptake inhibitors (SSRIs). Recent research involving serotonin aims to improve the safety and effe...
European Journal of Pharmacology, 2001
To examine further the hypothesis that the magnitude of the intrinsic activity of agonists at 5-HT receptors determines the 1A magnitude of their psychotropic activity, we studied the relationship between the maximal receptor activation produced by various Ž . 5-HT receptor ligands and their antidepressant-like effects i.e., decreased immobility in the forced swimming test in rats . Using three 1A different in vitro assays suitable to measure differences among high, intermediate, and low efficacy 5-HT receptor agonists, ligands 1A 1A w 35 x Ž .
Role of Serotonin-2A Receptors in Pathophysiology and Treatment of Depression
This chapter aims to summarize the up-today evidence-based biomedical knowledge on serotonin-2A (5-HT 2A) receptors and their role in pathophysiology and treatment of central nervous system (CNS) disorders, with a primary focus on depression. The first paragraph provides a brief introduction to serotonin (5-HT) system and 5-HT receptors, focusing on serotonin-2 (5-HT2) family and 5-HT2A receptor specifically. The second paragraph is focused on molecular genetics of 5-HT2A receptors, polymorphism of 5-HT2A receptor (5HT2AR) gene, 5HT2AR gene epigenetic mechanisms, such as DNA methylation, and post-translational modifications of 5-HT2AR messenger ribonucleic acid (mRNA), such as alternative splicing. The molecular and cellular pharmacology and physiology of 5-HT2A receptors in normal and pathological conditions are discussed in the third paragraph. The 5-HT2A receptors-acting ligands are addresses. The fourth paragraph describes the role of 5-HT receptors in the interaction between 5-HT and other neurotransmitter systems in health and in CNS disorders. The fifth and the final paragraph specifically deals with the role of 5-HT2A receptor in pathophysiology and treatment of depression, focusing on the 5-HT2A receptor expressed in the hippocampus.
Adaptive mechanisms following antidepressant drugs: Focus on serotonin 5-HT2A receptors
Pharmacological Reports, 2019
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