Preclinical and clinical characterization of the selective 5-HT(1A) receptor antagonist DU-125530 for antidepressant treatment

BACKGROUND AND PURPOSE The antidepressant efficacy of selective 5-HT reuptake inhibitors (SSRI) and other 5-HT-enhancing drugs is compromised by a negative feedback mechanism involving 5-HT(1A) autoreceptor activation by the excess 5-HT produced by these drugs in the somatodendritic region of 5-HT neurones. 5-HT(1A) receptor antagonists augment antidepressant-like effects in rodents by preventing this negative feedback, and the mixed β-adrenoceptor/5-HT(1A) receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5-HT(1A) autoreceptors. However, it is unclear whether 5-HT(1A) receptor antagonists not discriminating between pre- and post-synaptic 5-HT(1A) receptors would be clinically effective. EXPERIMENTAL APPROACH We characterized the pharmacological properties of the 5-HT(1A) receptor antagonist DU-125530 using receptor autoradiography, intracerebral microdialysis and electrophysiological recordings. Its capacity to accelerate/enhance the clinical effects of fluoxetine was assessed in a double-blind, randomized, 6 week placebo-controlled trial in 50 patients with major depression (clinicaltrials.gov identifier NCT01119430). KEY RESULTS DU-125530 showed equal (low nM) potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT(1A) receptors in rat and human brain. It antagonized suppression of 5-hydroxytryptaminergic activity evoked by 8-OH-DPAT and SSRIs in vivo. DU-125530 augmented SSRI-induced increases in extracellular 5-HT as effectively as in mice lacking 5-HT(1A) receptors, indicating a silent, maximal occupancy of pre-synaptic 5-HT(1A) receptors at the dose used. However, DU-125530 addition to fluoxetine did not accelerate nor augment its antidepressant effects. CONCLUSIONS AND IMPLICATIONS DU-125530 is an excellent pre- and post-synaptic 5-HT(1A) receptor antagonist. However, blockade of post-synaptic 5- HT(1A) receptors by DU-125530 cancels benefits obtained by enhancing pre-synaptic 5-hydroxytryptaminergic function.     

Dopamine uptake inhibitory activity of novel tryptamine 5-HT1 receptor ligands

In the search for novel serotonin receptor ligands, a series of 5-thiazolyl-N,N-dimethyltryptamine derivatives was synthesized which exhibited high affinity binding to 5-HT_1A, 5-HT_1B, and 5-HT_1D receptors and the functional characteristics of receptor agonists. One member, 5-(4-anilnomethyl-2-thiazolyl)-N,N-dimethyltryptamine (CP-110,330), was found also to be a potent and selective inhibitor of dopamine uptake in rat striatal synaptosomes. This activity was confirmed by its potent displacement of [³H]N(1-[2-benzo(b)thiophenyl]cyclohexyl piperidine (BTCP) binding to the dopamine transporter in striatal membranes. A limited structure-activity study indicated that optimal dopamine uptake blocking activity was obtained when the thiazole C4 substituent consisted of phenyl with a 2-atom spacer. The potent effect of these 5-HT₁ receptor ligands on dopamine uptake can be rationalized by the observation that the flexibility of these tryptamine molecules allows the superimposition of the phenyl ring and amino group of the side chain with the corresponding moieties of tametraline, a known catecholamine uptake inhibitor of fixed conformation. A related compound, 3-(R-N-methyl-2-pyrrolidinylmethyl)-5-(4-benzyl-2-thiazolylamino)-1H-indole (CP-146,662) showed similar potent binding affinity to 5-HT₁ receptors and the dopamine transporter. Compounds with this dual serotonergic and dopaminergic activity may have utility as antidepressant agents. As potent dopamine uptake inhibitors, they may also have application in the treatment of cocaine addiction. © 1994 Wiley-Liss, Inc.     

WAY-200070, a selective agonist of estrogen receptor beta as a potential novel anxiolytic/antidepressant agent

Recent studies have reported that estrogen has antidepressant-like effects in animal models. In this study we used the highly selective ERβ agonist, WAY-200070, to examine the role of ERβ activation on brain neurochemistry and activity in antidepressant and anxiolytic models in male mice. Within 15 min of administration, WAY-200070 (30 mg/kg s.c.) caused the nuclear translocation of striatal ERβ receptors from the cytosol. WAY-200070 also increased c-fos activation 4 h, but not 15 min after administration. Both nuclear translocation and c-fos induction effects of WAY-200070 demonstrate that WAY-200070 has bound to estrogen receptors and triggered downstream events. The absence of these effects in the ERβKO mice confirms that WAY-200070 was targeting ERβ. Administration of WAY-200070 (30 mg/kg s.c.) produced a delayed 50% increase in dopamine in the striatum of wild type mice. The effect was significant and maintained from 90 to 240 min. This increase was absent in ERβKO mice. In wild type mice, WAY-200070 (30 mg/kg s.c.) also produced a delayed and transient 100% increase in 5-HT. To further investigate the role of ERβ receptors on serotonergic function, 5-HTP accumulation was measured. ERβKO mice were found to have reduced frontal cortex levels of 5-HTP, indicating reduced tryptophan hydroxylase activity. WAY-200070 (3–30 mg/kg s.c.) was also tested in behavioural models. WAY-200070 (30 mg/kg s.c.) reduced immobility time in the mouse tail suspension test indicating an antidepressant-like effect. WAY-200070 (30 mg/kg) showed anxiolytic-like effects in the four-plate test (increased punished crossings) and stress-induced hyperthermia (attenuation of hyperthermic response).

The effects of the selective ERβ agonist, WAY-200070, on dopamine and serotonin, the anxiolytic-like and antidepressant-like effects as well as the genotype specific effects on neurochemistry support that positive modulation of ERβ function may provide a novel treatment for affective disorders.     

新型抗抑郁药：米那普仑

米那普仑是一种新型抗抑郁药,对5-羟色胺(5-HT)及去甲肾上腺素(NE)的再摄取具有双重抑制作用,且强度相当。口服米那普仑具有较高的生物利用度和较低的血浆蛋白结合力,大部分以原型或葡萄糖酸苷的形式从尿中清除,与其他药物相互作用少。米那普仑的抗抑郁疗效与三环类相似,可能优于选择性5-羟色胺回收抑制剂(SSRIs),且耐受性良好。每日2次口服,50～150 mg·d~(-1)。该药为抑郁症的药物治疗提供了一种新的选择。     

Antidepressant-like effects of a novel 5-HT3 receptor antagonist 6z in acute and chronic murine models of depression

Aim:

To investigate the antidepressant-like effects of a novel 5-HT₃ receptor antagonist N-(benzo[d]thiazol-2-yl)-3-methoxyquinoxalin-2-carboxamide (6z) in acute and chronic murine models of depression.

Methods:

5-HT₃ receptor antagonism was examined in guinea pig ileum in vitro. A tail suspension test (TST) was used as acute depression model to evaluate the antidepressant-like behavior in mice treated with 6z (0.5–2 mg/kg, ip). In chronic depression model, mice were exposed to a 4-week chronic unpredictable stress (CUS) protocol, and treated with 6z (0.5–2 mg·kg⁻¹·d⁻¹, po) or a positive drug fluoxetine (10 mg·kg⁻¹·d⁻¹, po) in the last 2 weeks, followed by behavioral and biochemical assessments.

Results:

The 5-HT₃ receptor antagonism of 6z (pA₂=7.4) in guinea pig ileum was more potent than that of a standard 5-HT₃ receptor antagonist ondansetron (pA₂=6.9). In acute depression model, 6z administration significantly decreased the immobility duration. In chronic depression model, 6z administration reversed CUS-induced depressive-like behavior, as evidenced by increased immobility duration in the forced swim test and sucrose preference in the sucrose preference test. Furthermore, chronic administration of 6z prevented CUS-induced brain oxidative stress, with significant reduction of pro-oxidant markers and elevation of antioxidant enzyme activity. Moreover, chronic administration of 6z attenuated CUS-induced hypothalamic-pituitary-adrenal axis hyperactivity, as shown by reduced plasma corticosterone levels. Similar results were observed in the fluoxetine-treated group.

Conclusion:

6z is a novel 5-HT₃ receptor antagonist with potential antidepressant-like activities, which may be related to modulating hypothalamic-pituitary-adrenal axis and attenuating brain oxidative damage.     

Preferential in vivo action of F15599, a novel 5-HT1A receptor agonist, at postsynaptic 5-HT1A receptors

Background and purpose:

{"type":"entrez-nucleotide","attrs":{"text":"F15599","term_id":"1130739","term_text":"F15599"}}F15599, a novel 5-hydroxytryptamine (5-HT)_1A receptor agonist with 1000-fold selectivity for 5-HT compared with other monoamine receptors, shows antidepressant and procognitive activity at very low doses in animal models. We examined the in vivo activity of {"type":"entrez-nucleotide","attrs":{"text":"F15599","term_id":"1130739","term_text":"F15599"}}F15599 at somatodendritic autoreceptors and postsynaptic 5-HT_1A heteroreceptors.

Experimental approach:

In vivo single unit and local field potential recordings and microdialysis in the rat.

Key results:

{"type":"entrez-nucleotide","attrs":{"text":"F15599","term_id":"1130739","term_text":"F15599"}}F15599 increased the discharge rate of pyramidal neurones in medial prefrontal cortex (mPFC) from 0.2 µg·kg⁻¹ i.v and reduced that of dorsal raphe 5-hydroxytryptaminergic neurones at doses >10-fold higher (minimal effective dose 8.2 µg·kg⁻¹ i.v.). Both effects were reversed by the 5-HT_1A antagonist (±)WAY100635. {"type":"entrez-nucleotide","attrs":{"text":"F15599","term_id":"1130739","term_text":"F15599"}}F15599 did not alter low frequency oscillations (∼1 Hz) in mPFC. In microdialysis studies, {"type":"entrez-nucleotide","attrs":{"text":"F15599","term_id":"1130739","term_text":"F15599"}}F15599 increased dopamine output in mPFC (an effect dependent on the activation of postsynaptic 5-HT_1A receptors) with an ED₅₀ of 30 µg·kg⁻¹ i.p., whereas it reduced hippocampal 5-HT release (an effect dependent exclusively on 5-HT_1A autoreceptor activation) with an ED₅₀ of 240 µg·kg⁻¹ i.p. Likewise, application of {"type":"entrez-nucleotide","attrs":{"text":"F15599","term_id":"1130739","term_text":"F15599"}}F15599 by reverse dialysis in mPFC increased dopamine output in a concentration-dependent manner. All neurochemical responses to {"type":"entrez-nucleotide","attrs":{"text":"F15599","term_id":"1130739","term_text":"F15599"}}F15599 were prevented by administration of (±)WAY100635.

Conclusions and implications:

These results indicate that systemic administration of {"type":"entrez-nucleotide","attrs":{"text":"F15599","term_id":"1130739","term_text":"F15599"}}F15599 preferentially activates postsynaptic 5-HT_1A receptors in PFC rather than somatodendritic 5-HT_1A autoreceptors. This regional selectivity distinguishes {"type":"entrez-nucleotide","attrs":{"text":"F15599","term_id":"1130739","term_text":"F15599"}}F15599 from previously developed 5-HT_1A receptor agonists, which preferentially activate somatodendritic 5-HT_1A autoreceptors, suggesting that {"type":"entrez-nucleotide","attrs":{"text":"F15599","term_id":"1130739","term_text":"F15599"}}F15599 may be particularly useful in the treatment of depression and of cognitive deficits in schizophrenia.     

Prenatal exposure of rats to antidepressant drugs down-regulates beta-adrenoceptors and 5-HT2 receptors in cerebral cortex. Lack of correlation between 5-HT2 receptors and serotonin-mediated behaviour

Changes in the binding of beta-adrenoceptors and 5-HT2 receptors and in behaviour mediated by serotonin were studied after either acute treatment or prenatal exposure of rats to antidepressant drugs. Chlorimipramine, iprindole and mianserin reduced the density of [3H]dihydroalprenolol-labelled beta-adrenoceptors and of [3H]spiperone-labelled 5-HT2 receptors in 25-day-old rats after prenatal exposure to these drugs from gestational day 6 to delivery. Prenatal exposure to nomifensine reduced also the number of beta-adrenoceptors but, in contrast, the density of 5-HT2 receptors and the KD for binding of [3H]spiperone were markedly increased. Acute treatment of 25-day-old rats with the same antidepressants did not modify in any case the characteristics of binding to beta-adrenergic or 5-HT2 receptors. The behavioural syndrome induced by 5-hydroxytryptophan and clorgyline was only antagonized on acute treatment by mianserin. Chronic treatment in utero with the antidepressants produced varied effects on the serotonin syndrome and there was no correlation between the number of 5-HT2 receptors and the intensity of the behaviour mediated by serotonin. The observed changes in beta-adrenergic and 5-HT2 receptors after prenatal exposure to antidepressant drugs appear to be more marked and longer-lasting than those induced by chronic treatment of adult rats.     

度洛西汀：一种新型抗抑郁药

度洛西汀是一种新型的抗抑郁药,为5-羟色胺和去甲肾上腺素再摄取的双重抑制剂。目前发现不仅可以治疗抑郁症,还可用于治疗压力性尿失禁与糖尿病周围神经病性疼痛。对于抑郁症伴发慢性疼痛也有一定的疗效。常见不良反应为：恶心、口干、失眠、头晕、便秘、食欲减退、乏力及嗜睡等。本文就近年来该药的研究进展作一综述。     

Behavioral pharmacological properties of the novel antidepressant paroxetine, a selective 5-HT uptake inhibitor

The behavioral effects of paroxetine were investigated in mice and rats in comparison with imipramine and amitriptyline. 1) Locomotor activities were decreased by imipramine and amitriptyline but not by paroxetine in both animal species. 2) Paroxetine antagonized methamphetamine-induced hyperactivity in mice as did imipramine and amitriptyline. 3) Paroxetine showed a more potent antimuricidal effect in raphe-lesioned rats than imipramine and amitriptyline, and it also inhibited muricide in olfactory bulbectomized rats. 4) The immobility of rats in the forced swimming test was markedly decreased by imipramine and amitriptyline, but only slightly by paroxetine. 5) Like imipramine and amitriptyline, paroxetine potentiated the methamphetamine- or L-DOPA-induced stereotyped sniffing, and it inhibited oxotremorine-induced tremor. 6) Paroxetine antagonized reserpine-induced hypothermia, tetrabenazine-induced ptosis, and enhanced ether-induced anesthesia, all less potently than imipramine and amitriptyline. 7) The analgesic action of paroxetine was stronger than that of imipramine and amitriptyline. 8) Paroxetine did not antagonize maximal electroshock- or pentetrazol-induced convulsions and haloperidol- or THC-induced catalepsy in rats. In addition, paroxetine neither exerted muscle relaxation nor affected the shuttle-box type conditioned avoidance in rats. From these results, the behavioral effects of paroxetine, as compared with imipramine and amitriptyline, were characterized by its potent antimuricidal action in raphe-lesioned rats and its weak effect in the forced swimming test and by its less potent muscle relaxant, anticonvulsant, anticataleptic and anesthesia-potentiating actions.     

Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466.

One of the most recently identified serotonin (5-hydroxytryptamine (5-HT)) receptor subtypes is the 5-HT6 receptor. Although in-depth localization studies reveal an exclusive distribution of 5-HT6 mRNA in the central nervous system, the precise biological role of this receptor still remains unknown. In the present series of experiments, we report the pharmacological and neurochemical characterization of two novel and selective 5-HT6 receptor agonists. WAY-181187 and WAY-208466 possess high affinity binding (2.2 and 4.8 nM, respectively) at the human 5-HT6 receptor and profile as full receptor agonists (WAY-181187: EC50=6.6 nM, Emax=93%; WAY-208466: EC50=7.3 nM; Emax=100%). In the rat frontal cortex, acute administration of WAY-181187 (3-30 mg/kg, subcutaneous (s.c.)) significantly increased extracellular GABA concentrations without altering the levels of glutamate or norepinephrine. Additionally, WAY-181187 (30 mg/kg, s.c.) produced modest yet significant decreases in cortical dopamine and 5-HT levels. Subsequent studies showed that the neurochemical effects of WAY-181187 in the frontal cortex could be blocked by pretreatment with the 5-HT6 antagonist, SB-271046 (10 mg/kg, s.c.), implicating 5-HT6 receptor mechanisms in mediating these responses. Moreover, the effects of WAY-181187 on catecholamines were attenuated by an intracortical infusion of the GABA A receptor antagonist, bicuculline (10 microM), confirming a local relationship between 5-HT6 receptors and GABAergic systems in the frontal cortex. In the dorsal hippocampus, striatum, and amygdala, WAY-181187 (10-30 mg/kg, s.c.) elicited robust elevations in extracellular levels of GABA without producing similar effects on concentrations of norepinephrine, serotonin, dopamine, or glutamate. In contrast to these brain regions, WAY-181187 had no effect on the extracellular levels of GABA in the nucleus accumbens or thalamus. Additional studies showed that WAY-208466 (10 mg/kg, s.c.) preferentially elevated cortical GABA levels following both acute and chronic (14 day) administration, indicating that neurochemical tolerance does not develop following repeated 5-HT6 receptor stimulation. In hippocampal slice preparations (in vitro), 5-HT(6) receptor agonism attenuated stimulated glutamate levels elicited by sodium azide and high KCl treatment. Furthermore, in the rat schedule-induced polydipsia model of obsessive compulsive disorder (OCD), acute administration of WAY-181187 (56-178 mg/kg, po) decreased adjunctive drinking behavior in a dose-dependent manner. In summary, WAY-181187 and WAY-208466 are novel, selective, and potent 5-HT6 receptor agonists displaying a unique neurochemical signature in vivo. Moreover, these data highlight a previously undescribed role for 5-HT6 receptors to modulate basal GABA and stimulated glutamate transmission, as well as reveal a potential therapeutic role for this receptor in the treatment of some types of anxiety-related disorders (eg OCD).     

Studies on the effects of 5-HT1A drugs in the pigeon

A number of compounds with high receptor binding affinity for the 5-hydroxytryptamine (5-HT) receptor subtype designated as 5-HT_1A can produce anxiolytic and/or antidepressant effects in humans. In contrast to the traditional benzodiazepine anxiolytics, many of the clinically efficacious 5-HT_1A drugs are either ineffective or produce inconsistent results in traditional preclinical anxiolytic screens using behavioral procedures with rodents. In preclinical antidepressant models with these animals, however, effects of the 5-HT_1A drugs, as well as those of traditional antidepressant compounds, are predictive of their antidepressant activity in humans. In contrast, 5-HT_1A drugs are quite effective in pigeons studied under a rather conventional punishment or conflict-type procedure that is also sensitive to the benzodiazepine anxiolytics. However, traditional antidepressant compounds, such as the tricyclic drugs amitriptyline and imipramine, as well as the 5-HT reuptake blockers such as fluoxetine, do not show effects similar to the newer 5-HT_1A drugs in this procedure. Thus, in rodents, current antidepressant models are sensitive to drugs that appear to function through different mechanisms, whereas conflict-type procedures typically do not reveal anxiolytic-like effects with 5-HT_1A drugs. The pigeon conflict procedure, however, discriminates between the 5-HT_1A antidepressants and antidepressant drugs functioning through other systems, whereas the effects of known anxiolytics in this procedure are quite similar. Increases in punished responding with 5-HT_1A drugs correlates highly (r= +0.83) with affinity for the 5-HT_1A receptor in pigeons. This paper reviews behavioral studies conducted with the pigeon in which the focus has been on the analysis of 5-HT_1A compounds and addresses additional work that is required to answer many of the outstanding questions about this new class of anxiolytic and/or antidepressant drugs. © 1992 Wiley-Liss, Inc.     

SB-649915, a novel, potent 5-HT1A and 5-HT1B autoreceptor antagonist and 5-HT re-uptake inhibitor in native tissue

An increase in brain 5-HT levels is thought to be the key mechanism of action which results in an antidepressant response. It has been proven that selective serotonin re-uptake inhibitors are effective antidepressants but the delay to therapeutic onset of these agents is thought to be due to the time required for 5-HT1A, and possibly 5-HT1B, autoreceptor desensitisation. Therefore an agent incorporating 5-HT re-uptake inhibition coupled with 5-HT1A and/or 5-HT1B autoreceptor antagonism may provide a fast acting clinical agent. The current studies describe the in vitro profile of SB-649915 (6-[(1-{2-[(2-methylquinolin-5-yl)oxy]ethyl}piperidin-4-yl)methyl]-2H-1,4-benzoxazin-3(4H)-one), a novel compound which has high affinity for human recombinant 5-HT1A, 5-HT1B and 5-HT1D receptors (pKi values of 8.6, 8.0, 8.8, respectively) and the human recombinant 5-HT transporter (pKi value of 9.3). SB-649915 also displays high affinity for rat, guinea pig, mouse and marmoset native tissue 5-HT1A, 5-HT1B and 5-HT1D receptors and rat native tissue 5-HT transporters (pKi values>or=7.5). In functional [35S]GTPgammaS binding studies, SB-649915 (up to 1 microM) does not display intrinsic activity in HEK293 cells expressing human recombinant 5-HT1A receptors but acts as a partial agonist at human recombinant 5-HT1B and 5-HT1D receptors with intrinsic activity values of 0.3 and 0.7, respectively, as compared to the full agonist 5-HT. From Schild analysis, SB-649915 caused a concentration-dependent, rightward shift of 5-HT-induced stimulation of basal [35S]GTPgammaS binding in cells expressing human recombinant 5-HT1A or 5-HT1B receptors to yield pA2 values of 9.0 and 7.9, respectively. In electrophysiological studies in rat dorsal raphe nucleus, SB-649915 did not affect the cell firing rate up to 1 microM but attenuated (+)8-hydroxy-2-(di-n-propylamino) tetralin-induced inhibition of cell firing with an apparent pKb value of 9.5. SB-649915 (1 microM) significantly attenuated exogenous 5-HT-induced inhibition of electrically-stimulated [3H]5-HT release from guinea pig cortex. In studies designed to enhance endogenous 5-HT levels, and therefore increase tone at 5-HT1B autoreceptors, SB-649915 significantly potentiated [3H]5-HT release at 100 and 1000 nM. In LLCPK cells expressing human recombinant 5-HT transporters and in rat cortical synaptosomes, SB-649915 inhibited [3H]5-HT re-uptake with pIC50 values of 7.9 and 9.7, respectively. In summary, SB-649915 is a novel, potent 5-HT1A/1B autoreceptor antagonist and 5-HT re-uptake inhibitor in native tissue systems and represents a novel mechanism that could offer fast acting antidepressant action.     

S41744, a dual neurokinin (NK)1 receptor antagonist and serotonin (5-HT) reuptake inhibitor with potential antidepressant properties: A comparison to aprepitant (MK869) and paroxetine

Though neurokinin₁ (NK₁) receptors are implicated in depressed states and their treatment, selective antagonists have disappointed in clinical trials. Accordingly, we designed a novel ligand, S41744 (2-piperazin-1-yl-indan-2-carboxylic-acid-(3-chloro-5-fluoro-benzyl)-methyl-amide), which both blocks NK₁ receptors and interferes with serotonin (5-HT) reuptake. S41744 mimicked the selective antagonist aprepitant in binding human (h)NK₁ receptors and in antagonising Substance-P-mediated Extracellular-Regulated-Kinase phosphorylation (pK_B, 7.7). Further, it dose-dependently (0.63–40.0 mg/kg, i.p.) displaced ex vivo [³H]-[Sar⁹,Met(O₂)¹¹]-Substance P binding to gerbil striatum, attenuated formalin-induced hind-paw licking in gerbils, and antagonised locomotion induced by i.c.v. administration of the NK₁ agonist GR73632 to guinea pigs. Like paroxetine, S41744 recognised h5-HT transporters, reduced synaptosomal uptake of 5-HT (pK_B, 7.9), and dose-dependently (0.63–10.0 mg/kg) elevated dialysis levels of 5-HT in the hippocampus and frontal cortex of freely-moving guinea pigs. Further, S41744 increased extracellular levels of 5-HT in frontal cortex and hippocampus of rats to a greater extent than paroxetine, and its inhibitory influence upon serotonergic perikarya was blunted relative to its affinity for 5-HT transporters. S41744 more potently blocked stress-induced vocalizations in guinea pigs than aprepitant and paroxetine, and it was active in forced-swim and marble-burying procedures of putative antidepressant properties in mice. While aprepitant displayed anxiolytic actions in stress-induced foot-tapping and social interaction tests in gerbils, paroxetine was anxiogenic and S41744 “neutral”, reflecting balanced NK₁ antagonism and suppression of 5-HT reuptake. Moreover, S41744 shared anxiolytic actions of aprepitant in the rat Vogel Conflict Test. In conclusion, S41744 is an innovative NK₁ antagonist/5-HT reuptake inhibitor justifying further evaluation for treatment of stress-related disorders.     

Chronic fluoxetine-induced desensitization of 5-HT1A and 5-HT1B autoreceptors: regional differences and effects of WAY-100635

Desensitization of 5-HT(1A) and 5-HT(1B) autoreceptors is thought to be the mechanism underlying the therapeutic effects of fluoxetine and other selective serotonin reuptake inhibitors when these are administered chronically. The blockade of 5-HT(1A) autoreceptors occurring on administration of a selective serotonin reuptake inhibitor together with a 5-HT(1A) autoreceptor antagonist is responsible for the acute increase in 5-hydroxytryptamine (serotonin, 5-HT) levels observed under these circumstances. The effects of repeated administration of selective serotonin reuptake inhibitors together with 5-HT(1A) receptor antagonists have not been widely studied. In this work, we found that the effects of fluoxetine (5 mg/kg, i.p., daily for 12 days) to desensitize 5-HT(1B) autoreceptors in the frontal cortex, as measured by the effect of the locally administered 5-HT(1B) receptor agonist, 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (CP 93129), and to desensitize 5-HT(1A) autoreceptors as measured by the action of the 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 50 microg/kg, s.c.) to reduce 5-HT levels in cortex, were prevented by concomitant administration of the 5-HT(1A) receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (WAY-100635; 0.3 mg/kg, s.c.). 5-HT(1B) receptor activity in the hypothalamus, as measured by the effects of locally administered CP 93129, and 5-HT(1A) autoreceptor activity, as determined by the effects of subcutaneous 8-OH-DPAT to reduce 5-HT levels in hypothalamus, were not altered either by fluoxetine alone or by fluoxetine in the presence of WAY-100635. The data suggest that the regulation of extracellular levels of 5-HT in the cortex and hypothalamus is subject to different autoregulatory mechanisms.     

Decrease of the platelet 5-HT2A receptor function by long-term imipramine treatment in endogenous depression

BACKGROUND: Animal studies have found that many antidepressants induce decreases in both the density and the functional activity of the serotonin 2A (5-HT2A) receptor subtype. However, the extrapolation of findings to humans has been inconclusive. A physiological platelet response mediated by this receptor, the serotonin-amplified platelet aggregation, was measured to study whether long-term antidepressant treatment induces changes in 5-HT2A receptor functioning in endogenous depressed patients. METHOD: The percentage of serotonin-amplified platelet aggregation to adenosine diphosphate (ADP) was studied in 15 untreated patients with major depressive disorder (DSM-IV) with endogenous features (Newcastle scale). This index was used as an indirect measurement of the functional status of platelet 5-HT2A receptors. Aggregation studies were repeated once remission of the symptoms was achieved during treatment with imipramine (150-300 mg/day). A group of 15 concurrent normal subjects was used as a control. RESULTS: A statistically significant decrease (p = 0.038) in the percentage of serotonin-amplified platelet aggregation to ADP was observed when remission was achieved (after 145 +/- 27 days). CONCLUSIONS: The results showed a decrease in a platelet functional response mediated by 5-HT2A receptors following effective imipramine treatment, suggesting that desensitization or down-regulation of the 5-HT2A receptor function could be linked to the therapeutic effect of some antidepressants. The data also support the use of platelet aggregometry as a surrogate measurement of antidepressant action, particularly in intra-subject designs.     

The therapeutic potential of 5-HT1A receptors: a patent review

Introduction: The 5-HT_1A receptors are implicated in mood disorders (anxiety, depression), in cognition, and in modulation of pain. Nearly 30 years of research in this field, there is still interest in developing new chemical entities capable of 5-HT_1A receptor activation or blockade.

Areas covered: This review article will highlight and review the research advances published in the patent literature between January 2007 and December 2011, giving emphasis to the medicinal chemist's standpoint. Literature search methodology included search in Scifinder and PubMed Databases and browsing clinicaltrials.gov website.

Expert opinion: Almost no new therapeutic applications have been proposed for molecules targeting the 5-HT_1A receptor, during the years covered by the present review. The discovery that stimulation of 5-HT_1A receptor can promote neurogenesis will likely renew the interest for selective 5-HT_1A receptor agonists as therapeutics to replace neural populations damaged by disease or injury.     

Specific inhibitory action of a novel antidepressant paroxetine on 5-HT uptake

Effect of a novel antidepressant, paroxetine, on the uptake of serotonin (5-HT), noradrenaline (NA) and dopamine (DA) as well as on various neuro-receptors were investigated in comparison with those of the tricyclic antidepressants amitriptyline, chlorimipramine and imipramine. Paroxetine showed a potent 5-HT uptake inhibitory action, giving the NA/5-HT ratio of 886 in comparison with the ratios of 1.7, 15 and 1.5 for amitriptyline, chlorimipramine and imipramine, respectively. On the other hand, paroxetine showed almost no inhibitory action on the binding of the [3H]-labeled ligands examined in this study [( 3H]quinuclidinyl benzilate, [3H]5-HT, [3H]ketanserine, [3H]pyrilamine, [3H]dihydroalprenolol, [3H]prazosin, [3H]clonidine and [3H]spiroperidol). In contrast, the tricyclic antidepressants showed inhibitory action on a number of bindings and also revealed comparatively high affinities especially for muscarine, histamine-1 and alpha 1-adrenaline receptors responsible for the side effects. From the above findings, it can be concluded that paroxetine has only a weak affinity for various neuro-receptors and inhibits specifically 5-HT uptake.     

Behavior selectively elicited by novel stimuli: modulation by the 5-HT1A agonist 8-OHDPAT and antagonist WAY-100635

The serotonergic system has a broad influence on behavior, but its specific contribution to novel object exploration remains to be examined. Toward this end, we assessed the impact of the 5-HT1A agonist, 8-OHDPAT (0.01-0.05 mg/kg) and the 5-HT1A antagonist, WAY-100635 (0.01-0.05 mg/kg) on novel object exploration in a familiar open-field environment. 8-OHDPAT produced a dose-related inhibition of responding to the novel object, whereas, WAY-100635 treatment induced a dose-related increase in the investigatory response to the novel object. Combined, the effects of WAY and 8-OHDPAT treatments were statistically indistinguishable from saline. In terms of locomotor activity, only the highest dose of 8-OHDPAT (0.05 mg/kg) altered locomotor activity and the effect was inhibitory. These findings provide evidence for an involvement of the serotonergic system in the response to novel stimuli and indicate that this effect can be dissociated from effects on overall activity including locomotor, rearing and grooming behaviors.     

Pharmacological characterization of RP 62203, a novel 5-hydroxytryptamine 5-HT2 receptor antagonist.

1. RP 62203 (2-[3-(4-(4-fluorophenyl)-piperazinyl)propyl]naphto[1,8- ca]isothiazole-1,1-dioxide) is a novel naphtosultam derivative which shows very high affinity for 5-HT2 receptors in the rat cerebral cortex (Ki = 50.0 pM). 2. RP 62203 is relatively selective for this sub-type of 5-hydroxytryptamine (5-HT) receptor, having lower affinity for the 5-HT1A receptor and very low affinity for the 5-HT, receptor. RP 62203 displayed low to moderate affinity for alpha 1-adrenoceptors, dopamine D2 receptors and histamine H1 receptors. 3. In vivo binding experiments demonstrated that oral administration of low doses of RP 62203 led to a long-lasting (greater than 6 h) occupation of cortical 5-HT2 receptors (ID50 = 0.39 mgkg-1). 4. In cortical slices from the neonatal rat, RP 62203 potently inhibited inositol phosphate formation evoked by 5-HT, with an IC50 of 7.76 nM. 5. The activity of neurones in the raphé and their responses to microiontophoretically applied 5-HT were studied with extracellular recording electrodes in the anaesthetized rat. RP 62203 potently and dose-dependently blocked excitations evoked by 5-HT when administered at doses of 0.5-4.0 mg kg-1, i.p. In contrast, neither 5-HT-evoked depressions nor glutamate-evoked excitations of raphé neuronal firing were blocked by RP 62203 at doses as high as 8.0 mg kg-1, i.p. 6. Head twitches induced by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) could be abolished by low doses of RP 62203 in mice (ED50 = 0.44 mg kg-1, p.o.) and in rats (ED50 = 1.54 p.o.). Similar results were obtained with mescaline and 5-hydroxytryptophan (5-HTP). 7. The potency of RP 62203 was compared with that of three other 5-HT2 receptor antagonists, ritanserin, ICI 169,369 and ICI 170,809. In all models, RP 62203 showed similar activity to ritanserin, whilst either ICI 169,369 or ICI 170,809 was several fold less active. 8. It is concluded that RP 62203 is a potent and selective antagonist at 5-HT2 receptors in the rodent central nervous system.