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1.
The role of 5-HT 7 receptor has been demonstrated in various animal models of mood disorders; however its function in cognition remains largely speculative. This study evaluates the effects of SB-269970, a selective 5-HT 7 antagonist, in a translational model of working memory deficit and investigates whether it modulates cortical glutamate and/or dopamine neurotransmission in rats. The effect of SB-269970 was evaluated in the delayed non-matching to position task alone or in combination with MK-801, a non-competitive NMDA receptor antagonist, and, in separate experiments, with scopolamine, a non-selective muscarinic antagonist. SB-269970 (10 mg/kg) significantly reversed the deficits induced by MK-801 (0.1 mg/kg) but augmented the deficit induced by scopolamine (0.06 mg/kg). The ability of SB-269970 to modulate MK-801-induced glutamate and dopamine extracellular levels was separately evaluated using biosensor technology and microdialysis in the prefrontal cortex of freely moving rats. SB-269970 normalized MK-801 -induced glutamate but not dopamine extracellular levels in the prefrontal cortex. Rat plasma and brain concentrations of MK-801 were not affected by co-administration of SB-269970, arguing for a pharmacodynamic rather than a pharmacokinetic mechanism. These results indicate that 5-HT 7 receptor antagonists might reverse cognitive deficits associated with NMDA receptor hypofunction by selectively normalizing glutamatergic neurotransmission. 相似文献
2.
In humans, serotonin (5-HT) has been implicated in numerous physiological and pathological processes in the peripheral auditory
system. Dopamine (DA), another transmitter of the lateral olivocochlear (LOC) efferents making synapses on cochlear nerve
dendrites, controls auditory nerve activation and protects the sensory nerve against overactivation. Using in vitro microvolume
superfusion techniques we tested 5-HT 6 and 5-HT 7 receptor antagonists whether they can influence dopamine (DA) release from the guinea-pig cochlea in control and in ischemic
conditions using currently available and new 5-HT 6 and 5-HT 7 antagonists and mixed antagonists, which were synthesized and characterized for the current study. While the 5-HT 7 antagonist SB-258719 was ineffective, SB-271046, which blocks the 5-HT 6 receptor, caused a significant increase in cochlear DA release what is contradictory with the excitatory nature of this type
of receptor. Moreover, the mixed 5-HT 6/7 antagonist EGIS-12233 induced an even more pronounced increase in the resting DA release. To understand why the block of
an excitatory receptor results in an increase instead of a decrease in function, we investigated the possible involvement
of an indirect neural mechanism through an inhibitory system. In the presence of the GABA A receptor blocker bicuculline, EGIS-12233 failed to increase the release of DA, suggesting that the serotonin receptor modulation
of DA release from the lateral olivocochlear efferents in the cochlea was produced indirectly by decreasing the GABAergic
inhibitory tone on dopaminergic nerve endings. The mixed 5-HT 7/D 4 receptor antagonist EGIS-11983 significantly increased both the stimulation-evoked and the resting DA release, while the
selective D4 blocker L-741,741 alone had no significant effect. Ischemia, simulated by oxygen and glucose deprivation from
the perfusion solution had no action on the effect of the drugs. Drugs that can increase the release of DA from LOC terminals
in the cochlea may have a role in the treatment of sensorineural hearing loss. 相似文献
3.
5-HT 7 receptor (5-HT 7R) is a promising target for the treatment of depression and neuropathic pain. 5-HT 7R antagonists exhibited antidepressant effects, while the agonists produced strong anti-hyperalgesic effects. In our efforts to discover selective 5-HT 7R antagonists or agonists, N-biphenylylmethyl 2-methoxyphenylpiperazinylalkanamides 1 were designed, synthesized, and biologically evaluated against 5-HT 7R. Among the synthesized compounds, N-2′-chlorobiphenylylmethyl 2-methoxyphenylpiperazinylpentanamide 1– 8 showed the best binding affinity with a Ki value of 8.69 nM and it was verified as a novel antagonist according to functional assays. The compound 1– 8 was very selective over 5-HT 1DR, 5-HT 2AR, 5-HT 3R, 5-HT 5AR and 5-HT 6R and moderately selective over 5-HT 1AR, 5-HT 1BR and 5-HT 2CR. The novel 5-HT 7R antagonist 1– 8 exhibited an antidepressant effect at a dose of 25 mg/kg in the forced swimming test in mice and showed a U-shaped dose–response curve which typically appears in 5-HT 7R antagonists such as SB-269970 and lurasidone. 相似文献
4.
1. The 5-HT 2 receptors subdivision into the 5-HT 2A/2B/2C subtypes along with the advent of the selective antagonists has allowed a more detailed investigation on the role and therapeutic significance of these subtypes in cognitive functions. The present study further analyzed the 5-HT 2 receptors role on memory consolidation.2. The SB-200646 (a selective 5-HT 2B/2C receptor antagonist) and LY215840 (a nonselective 5-HT 2/7 receptor antagonist) posttraining administration had no effect on an autoshaped memory consolidation. However, both drugs significantly and differentially antagonized the memory impairments induced by 1-(3-chlorophenyl)piperazine (mCPP), 1-naphtyl-piperazine (1-NP), mesulergine, or N-(3-trifluoromethylphenyl) piperazine (TFMPP).3. In contrast, SB-200646 failed to modify the facilitatory procognitive effect produced by (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) or ketanserin, which were sensitive to MDL100907 (a selective 5-HT 2A receptor antagonist) and to a LY215840 high dose.4. Finally, SB-200646 reversed the learning deficit induced by dizocilpine, but not that by scopolamine; while SB-200646 and MDL100907 coadministration reversed memory deficits induced by both drugs.5. It is suggested that 5-HT 2B/2C receptors might be involved on memory formation probably mediating a suppressive or constraining action. Whether the drug-induced memory impairments in this study are explained by simple agonism, antagonism, or inverse agonism at 5-HT 2 receptors remains unclear at this time.6. Notably, the 5-HT 2 receptor subtypes blockade may provide some benefit to reverse poor memory consolidation conditions associated with decreased cholinergic, glutamatergic, and/or serotonergic neurotransmission. 相似文献
5.
As part of our continuing efforts to identify therapeutics for CNS diseases, such as schizophrenia and Alzheimer’s disease (AD), we have been focused on the 5-HT 6 receptor in an attempt to identify ligands as a potential treatment for cognitive dysfunction. Herein we report the identification of a novel series of 1-sulfonylindazole derivatives as potent and selective 5-HT 6 antagonists. The synthesis and SAR of this class of compounds are reported. Several potent compounds in both binding and cyclase functional assays also display good selectivity, microsomal stability, solubility, and brain penetration as well as low cytochrome P450 inhibition. One compound exemplified in this series showed 24% oral bioavailability and in vivo efficacy in a NOR cognition model at 10 mg/kg following an oral administration in rats. 相似文献
6.
2-Amino-6-chloro-3,4-dihydroquinazoline HCl (A6CDQ, 4) binds at 5-HT 3 serotonin receptors and displays antidepressant-like action in the mouse tail suspension test (TST). Empirically, 4 was demonstrated to be a 5-HT 3 receptor antagonist (two-electrode voltage clamp recordings using frog oocytes; IC 50 = 0.26 μM), and one that should readily penetrate the blood–brain barrier (log P = 1.86). 5-HT 3 receptor antagonists represent a potential approach to the development of new antidepressants, and 4 is an example of a structurally novel 5-HT 3 receptor antagonist that is active in a preclinical antidepressant model (i.e., the mouse TST). 相似文献
7.
We found that Tyr-Leu (YL) dose-dependently exhibits potent anxiolytic-like activity (0.1-1 mg/kg, i.p.) comparable to diazepam in the elevated plus-maze test in mice. YL was orally active (0.3-3 mg/kg). A retro-sequence peptide or a mixture of Tyr and Leu was inactive. The anxiolytic-like activity of YL was inhibited by antagonists for serotonin 5-HT 1A, dopamine D 1 and GABA A receptors; however, YL had no affinity for them. We also determined the order of their activation is 5-HT 1A, D 1 and GABA A receptors using selective agonists and antagonists. Taken together, YL may exhibit anxiolytic-like activity via activation of 5-HT 1A, D 1 and GABA A receptors. 相似文献
8.
BackgroundThe role of the serotonin receptor 4 (5-HT 4R) pathway in cardiac excitation-contraction coupling (ECC) remains unclear. In the brain, induction of the calcium (Ca 2+)-binding protein p11 enhances 5-HT 4R translocation and signaling and could therefore be considered as a modulator of the 5-HT 4R pathway in the myocardium. p11 expression is increased by brain-derived neurotrophic factor (BDNF) or antidepressant drugs (imipramine). Thus, we investigated whether p11 regulates the 5-HT 4R pathway in the heart in physiological conditions or under pharmacological induction and the effects on calcium handling. Methods and resultsp11 expression was induced in vivo in healthy Wistar rats by imipramine (10 mg/kg/21 days) and in vitro in left ventricular cardiomyocytes exposed to BDNF (50 ng/ml/8 h). Cell shortening and real-time Ca 2+ measurements were processed on field-stimulated intact cardiomyocytes with the selective 5-HT 4R agonist, prucalopride (1 μM). Both imipramine and BDNF-induced cardiomyocyte p11 expression unmasked a strong response to prucalopride characterized by an increase of both cell shortening and Ca 2+ transient amplitude compared to basal prucalopride associated with a high propensity to trigger diastolic Ca 2+ events. Healthy rats treated with BDNF (180 ng/day/14 days) exhibited a sustained elevated heart rate following a single injection of prucalopride (0.1 mg/kg) which was not observed prior to treatment. ConclusionsWe have identified a novel role for p11 in 5-HT 4R signaling in healthy rat ventricular cardiomyocytes. Increased p11 expression by BDNF and imipramine unraveled a 5-HT 4R-mediated modulation of cardiac Ca 2+ handling and ECC associated with deleterious Ca 2+ flux disturbances. Such mechanism could partly explain some cardiac adverse effects induced by antidepressant treatments. 相似文献
9.
The synthesis and structure-activity relationship (SAR) of a novel series of aryl piperazine napthyridinone D 2 partial agonists is described. Our goal was to optimize the affinities for the D 2, 5-HT 2A and 5-HT 1A receptors, such that the D 2/5-HT 2A ratio was greater than 5 to ensure maximal occupancy of these receptors when the D 2 occupancy reached efficacious levels. This strategy led to identification of PF-00217830 ( 2) with robust inhibition of sLMA (MED = 0.3 mg/kg) and DOI-induced head twitches in rats (31% and 78% at 0.3 and 1 mg/kg) with no catalepsy observed at the highest dose tested (10 mg/kg). 相似文献
10.
The effects of two putative 5-HT 1A antagonists, 4-(2′-methoxyphenyl)-1-[2′-[N-(2″-pyridinyl)-p-iodobenzamido]ethyl]piperazine (p-MPPI) and 4-(2′-methoxyphenyl)-1-[2′-[N-(2″-pyridinyl)-p-flourobenzamido]ethyl]piperazine (p-MPPF), were examined in vivo in two tests of postsynaptic 5-HT 1A receptor activation, hypothermia and reciprocal forepaw treading, in the rat. Both p-MPPI (10 mg/Kg, I.p.) and p-MPPF (10 mg/Kg, I.p.) antagonized the hypothermia induced by the 5-HT 1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.5 mg/Kg, S.c.). Neither p-MPPI nor p-MPPF administered alone at a dose of 10 mg/kg (i.p.) induced hypothermia. Similarly, both p-MPPI (10 mg/Kg, I.p.) and p-MPPF (2.5 mg/Kg, I.p.) completely antagonized 8-OH-DPAT (2 mg/Kg, S.c.)-induced forepaw treading in rats pretreated with reserpine (1 mg/Kg, S.c., 18–24 hours prior to the experiment). p-MPPI and p-MPPF, at doses of 10 mg/kg (i.p.) did not induce forepaw treading in reserpine pretreated animals. The results of the present study demonstrate that p-MPPI and p-MPPF act as 5-HT 1A receptor antagonists in these measures of postsynaptic 5-HT 1A a receptor activation. 相似文献
11.
The N-alkylation of the sulfonamide moiety, in a group of arylsulfonamide derivatives of (aryloxy)ethyl piperidines, may be considered as a strategy for the design of selective 5-HT 7 receptor ligands or multifunctional agents to extend a polypharmacological approach to the treatment of complex diseases. The study allowed for the identification of 31 (1-methyl- N-{1-[2-(2-( t-butyl)phenoxy)ethyl]piperidin-4-yl}- N-cyclopropylmethyl-1 H-pyrazole-4-sulfonamide), a potent and selective 5-HT 7 receptor antagonist and 33 (1-methyl- N-{1-[2-(biphenyl-2-yloxy)ethyl]piperidin-4-yl}- N-cyclopropylmethyl-1 H-pyrazole-4-sulfonamide), as multimodal 5-HT/dopamine receptor ligand, as 5-HT 2A/5-HT 7/D 2 receptor antagonists. Both selected compounds were evaluated in vivo in a forced swim test (FST) in mice and in a novel object recognition (NOR) task in rats, demonstrating distinct antidepressant-like and pro-cognitive properties (MED = 1.25 mg/kg and 1 mg/kg, ip, respectively). These findings warrant further studies to explore the therapeutic potential of N-alkylated arylsulfonamides for the treatment of CNS disorders. 相似文献
12.
ABSTRACT The role of the serotonin 7 receptor (5-HT 7 receptor) subtype in a number of domains has been widely recognized, but its role in the regulation of changes of the circadian rhythm after anesthesia is still unclear. We used intraperitoneal injection of 5-HT 7 receptor agonist LP-211 or antagonist SB-269970 in mice to influence the level of 5-HT 7 receptor protein in the SCN and to observe the role of this receptor on circadian rhythm changes after isoflurane anesthesia. Our results show the appropriate dose of SB-269970 significantly alleviated the circadian rhythm disorder induced by isoflurane anesthesia, while LP-211 significantly aggravated it after anesthesia, which is different from the phase shift that can be caused by the administration of LP-211 before anesthesia. These findings may indicate the 5-HT 7 receptor plays a complex role in the regulation of circadian rhythm after anesthesia. Our findings may provide some positive significance for alleviating circadian rhythm disorder in patients after anesthesia and ultimately promoting rapid postoperative recovery. 相似文献
13.
AbstractUnbound drug concentration in the brain would be the true exposure responsible for specific target occupancy. Drug exposures from preclinical are total concentrations of those over/underestimate the clinical dose projection. With the application of mass spectrometry, the current work proposes a definite measure of test drug exposures at serotonin-2A occupancy. The 5-HT 2A occupancy of antagonist in the rat brain has determined with non-radiolabeled tracer MDL-100,907 at an optimized dose (3?µg/kg) and treatment time (30?min). Equilibrium dialysis method determines the in vitro free fraction of the test antagonist in untreated rat brain homogenates and plasma. Drug-free fractions derived the unbound concentration (EC 50) in plasma and brain at test doses. The corresponding binding affinities (Ki) correlated with the unbound concentrations. Except for quetiapine, the ED 50 values in the dose-occupancy curves of antagonists are close and ranged from 1 to 3?mg/kg. The test drug quetiapine, eplivanserin, and clozapine showed high free fractions in plasma, but for ketanserin and olanzapine, the brain free fraction was higher. The correlation between the unbound EC 50 of the antagonists and corresponding Ki values was good ( r2=0.828). The improved EC 50 accuracy with unbound concentrations was 10–250 folds in plasma and 10–170 folds in the brain. Further, the free fractions ( fu, plasma/ fu, brain) of test drugs had shown a correlation of ~83% with brain permeability ( Ctotal brain/ Ctotal plasma), a limiting factor. Thus, correlating the occupancy with unbound exposure and pharmacology would result in an accurate measurement of drug potency and optimizes in selecting the clinical dose. 相似文献
14.
AimsThe purpose of this study was to investigate the antinociceptive effect of epicatechin as well as the possible mechanisms of action in diabetic rats. Main methodsRats were injected with streptozotocin to produce hyperglycemia. The formalin test was used to assess the nociceptive activity. Key findingsAcute pre-treatment with epicatechin (0.03–30 mg/kg, i.p.) prevented formalin-induced nociception in diabetic rats. Furthermore, daily or every other day treatment for 2 weeks with epicatechin (0.03–30 mg/kg, i.p.) also prevented formalin-induced nociception in diabetic rats. Acute epicatechin-induced antinociception was prevented by l-NAME ( Nω-nitro-l-arginine methyl ester hydrochloride, 1–10 mg/kg, non-selective nitric oxide synthesis inhibitor), 7-nitroindazole (0.1–1 mg/kg, selective neuronal nitric oxide synthesis inhibitor), ODQ (1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one, 0.2–2 mg/kg, guanylyl cyclase inhibitor) or glibenclamide (1–10 mg/kg, ATP-sensitive K + channel blocker). Moreover, epicatechin (3 mg/kg)-induced antinociception was fully prevented by methiothepin (0.1–1 mg/kg, serotonergic receptor antagonist), WAY-100635 (0.03–0.3 mg/kg, selective 5-HT 1A receptor antagonist) or SB-224289 (0.03–0.3 mg/kg, selective 5-HT 1B receptor antagonist). In contrast, BRL-15572 (0.03–0.3 mg/kg, selective 5-HT 1D receptor antagonist) only slightly prevented the antinociceptive effect of epicatechin. Naloxone (0.1–1 mg/kg, opioid antagonist) did not modify epicatechin's effect. SignificanceData suggest the involvement of the nitric oxide–cyclic GMP–K + channel pathway as well as activation of 5-HT 1A and 5HT 1B, and at a lesser extent, 5-HT 1D, but not opioid, receptors in the antinociceptive effect of epicatechin in diabetic rats. Our data suggest that acute or chronic treatment with epicatechin may prove to be effective to treat nociceptive hypersensitivity in diabetic patients. 相似文献
15.
The present work evaluated the anxiolytic activity of an aqueous extract of Apocynum venetum L. (Apocynaceae) and bioguided its fractionation using the elevated plus maze (EPM) in mice as a model of anxiety. A single treatment of AV extract markedly increased the percentage time spent on the open arms of the EPM in two distinct concentration ranges of 22.5–30 and 100–125 mg/kg p.o., respectively, indicating a putative anxiolytic-like activity. Fractions showing anxiolytic effects in concentrations equal to 30 or 125 mg/kg of whole extract were antagonized using the benzodiazepine antagonist flumazenil (3 mg/kg i.p.) or the 5-HT 1A receptor antagonist WAY-100635 (0.5 mg/kg i.p.). All active fractions in a concentration equal to 125 mg/kg were effectively blocked by the benzodiazepine antagonist flumazenil, while the anxiolytic activities of fractions in the lower dose equivalent to 30 mg/kg of whole extract were inhibited by the 5-HT 1A receptor antagonist WAY-100635. Through further separation of AV fractions it was possible to isolate and characterize the flavonol kaempferol which showed an anxiolytic-like activity in concentrations from 0.02 to 1.0 mg/kg p.o. The anxiolytic activity of kaempferol was partially antagonized by concomitant administration of flumazenil, but not by WAY-100635. In conclusion, our study clearly demonstrates that AV extract possesses anxiolytic-like activity and that at least one of its flavonoids, kaempferol, can elicit the same kind of neuropharmacological activity. 相似文献
16.
The nociceptive effect of Levetiracetam (LEV) on the expression of 5-HT1A and 5-HT7 receptors found in the thalamus was evaluated. Thirty-six male rats (Wistar) were randomized into six groups: in the Control group without treatment; LEV50 group LEV was administered in a single dose of 50 mg/kg i.g.; in the LEV300 group LEV dose of 300 mg/kg i.g.; in the FORMALIN group the formalin test was performed; in the LEV50/FORMALIN group LEV dose of 50 mg/kg i.g and the formalin test was performed; in the LEV300/FORMALIN group LEV dose of 300 mg/kg i.g and the formalin test was performed, subsequently the thalamus was dissected in all groups. In the formalin tests LEV exhibited an antinociceptive effect in the LEV300/FORMALIN group (p?<?0.05) and a pronociceptive effect in the LEV50/FORMALIN group (p?<?0.001). The results obtained by Real-time PCR confirmed the expression of the 5-HT1A and 5-HT7 receptors in the thalamus, 5-HT1A receptors increased significantly in the FORMALIN group and the LEV300/FORMALIN group (p?<?0.05). 5-HT7 receptors are only over expressed at a dose of 300 mg/Kg of LEV with formalin (p?<?0.05). This suggests that LEV modulates the sensation of pain by controlling the expression of 5-HT1A and 5-HT7 in a tonic pain model, and that changes in the expression of 5-HT1A and 5-HT7 receptors are associated with the sensation of pain, furthermore its possibility to be used in clinical treatments for pain. 相似文献
17.
We describe the first validated scintillation proximity assay (SPA) binding method for quantitation of 3H-labeled d-lysergic acid diethylamide (LSD) binding to recombinant human 5-hydroxytryptamine 6 (5-HT 6) receptors expressed in Chinese hamster ovary (CHO)-Dukx and HeLa cells. The assay was developed using intact cells as a receptor source because membrane fractions derived from these cells failed to discern specific binding from a high level of nonspecific binding. The pharmacological binding profile of seven 5-HT 6 agonists and antagonists using intact CHO-Dukx/5-HT 6 cells in the SPA format was similar to data obtained from a filtration binding assay using HeLa/5-HT 6 membranes. Ki values and rank order of potencies obtained in the SPA format were consistent with published filtration data as follows: SB-271046 ( Ki = 1.9 nM) > methiothepin ( Ki = 6.2 nM) > mianserin ( Ki = 74.3 nM) > 5-methoxytryptamine (5-MeOT, Ki = 111 nM) > 5-HT ( Ki = 150 nM) > ritanserin ( Ki = 207 nM) > 5-carboxamidotryptamine (5-CT, Ki = 704 nM). Additional evaluation with four antipsychotics demonstrated strong agreement with previous literature reports. A high specific binding signal and low assay variability, as determined by Z′ = 0.81 ± 0.017, make the SPA format amenable to automation and higher throughput; hence, this assay can be a viable alternative to the more labor-intensive filtration and centrifugation methods. 相似文献
18.
(Piperazin-1-yl-phenyl)-arylsulfonamides were synthesized and identified to show high affinities for both 5-HT 2C and 5-HT 6 receptors. Among them, naphthalene-2-sulfonic acid isopropyl-[3-(4-methyl-piperazin-1-yl)-phenyl]-amide ( 6b) exhibits the highest affinity towards both 5-HT 2C (IC 50 = 4 nM) and 5-HT 6 receptors (IC 50 = 3 nM) with good selectivity over other serotonin (5-HT 1A, 5-HT 2A, and 5-HT 7) and dopamine (D 2–D 4) receptor subtypes. In 5-HT 2C and 5-HT 6 receptor functional assays, this compound showed considerable antagonistic activity for both receptors. 相似文献
19.
1-[2-(4-Methoxyphenyl)phenyl]piperazine ( 4) is a potent serotonin 5-HT 7 receptor antagonist ( Ki = 2.6 nM) with a low binding affinity for the 5-HT 1A receptor ( Ki = 476 nM). As a potential positron emission tomography (PET) radiotracer for the 5-HT 7 receptor, [ 11C] 4 was synthesized at high radiochemical yield and specific activity, by O-[ 11C]methylation of 2′-(piperazin-1-yl)-[1,1′-biphenyl]-4-ol ( 6) with [ 11C]methyl iodide. Autoradiography revealed that [ 11C] 4 showed in vitro specific binding with 5-HT 7 in the rat brain regions, such as the thalamus which is a region with high 5-HT 7 expression. Metabolite analysis indicated that intact [ 11C] 4 in the brain exceeded 90% of the radioactive components at 15 min after the radiotracer injection, although two radiolabeled metabolites were found in the rat plasma. The PET study of rats showed moderated uptake of [ 11C] 4 in the brain (1.2 SUV), but no significant regional difference in radioactivity in the brain. Pretreatment with 5-HT 7-selective antagonist SB269970 ( 3) did not decrease the uptake of [ 11C] 4 in the rat brain. Further studies are warranted that focus on the development of PET ligand candidates with higher binding affinity for 5-HT 7 and higher in vivo stability in brain than 4. 相似文献
20.
A series of 9-disubstituted N-(9 H-fluorene-2-carbonyl)guanidine derivatives have been discovered as potent and orally active dual 5-HT 2B and 5-HT 7 receptor antagonists. Upon screening several compounds, N-(diaminomethylene)-4′,5′-dihydro-3′ H-spiro[fluorene-9,2′-furan]-2-carboxamide ( 17) exhibited potent affinity for both 5-HT 2B ( Ki = 5.1 nM) and 5-HT 7 ( Ki = 1.7 nM) receptors with high selectivity over 5-HT 2A, 5-HT 2C, α 1, D 2 and M 1 receptors. Optical resolution of the intermediate carboxylic acid 16 via the formation of diastereomeric salts using chiral alkaloids gave the optically pure compounds ( R)- 17 and ( S)- 17. Both enantiomers suppressed 5-HT-induced dural protein extravasation in guinea pigs in a dose-dependent manner and the amount of leaked protein was suppressed to near normal levels when orally administrated at 10 mg/kg. ( R)- 17 and ( S)- 17 were therefore selected as candidates for human clinical trials. 相似文献
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