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1.
iScience ; 26(2): 105940, 2023 Feb 17.
Article in English | MEDLINE | ID: mdl-36718363

ABSTRACT

Malaria eradication requires the development of new drugs to combat drug-resistant parasites. We identified bisbenzylisoquinoline alkaloids isolated from Cocculus hirsutus that are active against Plasmodium falciparum blood stages. Synthesis of a library of 94 hemi-synthetic derivatives allowed to identify compound 84 that kills multi-drug resistant clinical isolates in the nanomolar range (median IC50 ranging from 35 to 88 nM). Chemical optimization led to compound 125 with significantly improved preclinical properties. 125 delays the onset of parasitemia in Plasmodium berghei infected mice and inhibits P. falciparum transmission stages in vitro (culture assays), and in vivo using membrane feeding assay in the Anopheles stephensi vector. Compound 125 also impairs P. falciparum development in sporozoite-infected hepatocytes, in the low micromolar range. Finally, by chemical pull-down strategy, we characterized the parasite interactome with trilobine derivatives, identifying protein partners belonging to metabolic pathways that are not targeted by the actual antimalarial drugs or implicated in drug-resistance mechanisms.

2.
Chemistry ; 25(11): 2745-2749, 2019 Feb 21.
Article in English | MEDLINE | ID: mdl-30600846

ABSTRACT

A strategy for the assembly of the entire carbon backbone of a stereoisomer of the antitumor marine natural product hemicalide has been investigated. The devised convergent approach relies on Horner-Wadsworth-Emmons and Julia-Kocienski olefination reactions for the construction of the C6=C7 and C34=C35 double bonds, respectively, an aldol reaction to create the C27-C28 bond, and a Suzuki-Miyaura cross-coupling as the endgame to form the C15-C16 bond.

3.
J Org Chem ; 83(11): 5975-5985, 2018 06 01.
Article in English | MEDLINE | ID: mdl-29715016

ABSTRACT

Verongidolide is a natural macrolactone recently isolated from a New Caledonia sponge, Verongidolae. The structure of this natural product is similar to the structure of superstolides, also isolated from a New Caledonian sponge, Neosiphonia superstes. From a biological point of view, verongidolide and superstolides A and B present potent cytotoxicity against human oral carcinoma KB (0.3 nM). By comparing the 1H NMR chemical shifts as well as the coupling constants, we conclude that verongidolide possesses a cis-decalin core and we hypothesize that the relative configuration of the cis-decalin core is similar to the one of superstolide A. To verify this hypothesis, intramolecular and transannular Diels-Alder reactions were attempted to construct the decalin core. Unexpectedly, the selectivity of the Diels-Alder reactions was exo and an in-depth DFT calculation of the key reaction mechanism was achieved in order to understand the factors controlling this unexpected selectivity.

4.
J Org Chem ; 81(24): 12275-12290, 2016 12 16.
Article in English | MEDLINE | ID: mdl-27978725

ABSTRACT

The synthesis of the C1-C27 fragment of hemicalide, a marine metabolite displaying a unique potent antiproliferative activity, has been accomplished. The synthetic approach highlights a remarkably efficient ring-closing metathesis reaction catalyzed by Nolan ruthenium indenylidene complexes to elaborate the highly substituted δ-lactone framework.

5.
Bioorg Med Chem ; 23(13): 3712-21, 2015 Jul 01.
Article in English | MEDLINE | ID: mdl-25937235

ABSTRACT

A screening program aimed at discovering novel anticancer agents based on natural products led to the selection of koningic acid (KA), known as a potent inhibitor of glycolysis. A method was set up to produce this fungal sesquiterpene lactone in large quantities by fermentation, thus allowing (i) an extensive analysis of its anticancer potential in vitro and in vivo and (ii) the semi-synthesis of analogues to delineate structure-activity relationships. KA was characterized as a potent, but non-selective cytotoxic agent, active under both normoxic and hypoxic conditions and inactive in the A549 lung cancer xenograft model. According to our SAR, the acidic group could be replaced to keep bioactivity but an intact epoxide is essential.


Subject(s)
Antineoplastic Agents/chemical synthesis , Lung Neoplasms/drug therapy , Animals , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Hypoxia , Cell Line, Tumor , Fermentation , Glycolysis/drug effects , Humans , Inhibitory Concentration 50 , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice , Mice, Nude , Sesquiterpenes/chemical synthesis , Sesquiterpenes/isolation & purification , Sesquiterpenes/pharmacokinetics , Sesquiterpenes/pharmacology , Structure-Activity Relationship , Trichoderma/chemistry , Trichoderma/metabolism , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
6.
Org Lett ; 17(10): 2446-9, 2015 May 15.
Article in English | MEDLINE | ID: mdl-25906322

ABSTRACT

The synthesis of five diastereomeric model compounds incorporating the C32-C46 segment of the antitumor marine natural product hemicalide has been achieved through a convergent approach relying on the 1,4-addition of an alkenyl boronate to an α,ß-unsaturated δ-lactone followed by α-hydroxylation of an enolate and a Julia-Kocienski olefination. Comparison of the (1)H and (13)C NMR data of the model compounds with those of hemicalide enabled the assignment of the relative configuration of the C36-C42 subunit.


Subject(s)
Antineoplastic Agents/chemical synthesis , Biological Products/chemical synthesis , Polyketides/chemistry , Polyketides/chemical synthesis , Antineoplastic Agents/chemistry , Biological Products/chemistry , Molecular Conformation , Stereoisomerism
7.
Phytochemistry ; 107: 97-101, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25172516

ABSTRACT

Four alkaloids named hosieines A-D were isolated from the root and stem of Ormosia hosiei. Their flat structures were established by mass spectrometry and by a combination of NMR experiments. These molecules probably share a common biosynthetic origin with the lupin alkaloids but they differ in the formation of the last ring, being here part of a rare 2-azabicyclo[3.2.1]octane system. Their absolute configuration was determined by X-ray crystallography using CuKα radiation. As has been described for cytisine, they display a remarkable affinity towards neuronal nicotinic acetylcholine α4ß2 receptor.


Subject(s)
Alkaloids/isolation & purification , Fabaceae/chemistry , Receptors, Nicotinic/drug effects , Alkaloids/chemistry , Alkaloids/pharmacology , Azocines/chemistry , Azocines/isolation & purification , Azocines/pharmacology , Crystallography, X-Ray , Molecular Conformation , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Plant Roots/chemistry , Plant Stems/chemistry , Quinolizines/chemistry , Quinolizines/isolation & purification , Quinolizines/pharmacology
8.
ChemMedChem ; 9(3): 590-601, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24678024

ABSTRACT

Quinoline derivative SGI-1027 (N-(4-(2-amino-6-methylpyrimidin-4-ylamino)phenyl)-4-(quinolin-4-ylamino)benzamide) was first described in 2009 as a potent inhibitor of DNA methyltransferase (DNMT) 1, 3A and 3B. Based on molecular modeling studies, performed using the crystal structure of Haemophilus haemolyticus cytosine-5 DNA methyltransferase (MHhaI C5 DNMT), which suggested that the quinoline and the aminopyridimine moieties of SGI-1027 are important for interaction with the substrates and protein, we designed and synthesized 25 derivatives. Among them, four compounds­namely the derivatives 12, 16, 31 and 32­exhibited activities comparable to that of the parent compound. Further evaluation revealed that these compounds were more potent against human DNMT3A than against human DNMT1 and induced the re-expression of a reporter gene, controlled by a methylated cytomegalovirus (CMV) promoter, in leukemia KG-1 cells. These compounds possessed cytotoxicity against leukemia KG-1 cells in the micromolar range, comparable with the cytotoxicity of the reference compound, SGI-1027. Structure­activity relationships were elucidated from the results. First, the presence of a methylene or carbonyl group to conjugate the quinoline moiety decreased the activity. Second, the size and nature of the aromatic or heterocycle subsitutents effects inhibition activity: tricyclic moieties, such as acridine, were found to decrease activity, while bicyclic substituents, such as quinoline, were well tolerated. The best combination was found to be a bicyclic substituent on one side of the compound, and a one-ring moiety on the other side. Finally, the orientation of the central amide bond was found to have little effect on the biological activity. This study provides new insights in to the structure-activity relationships of SGI-1027 and its derivative.


Subject(s)
Aminoquinolines/chemical synthesis , Aminoquinolines/pharmacology , DNA Methylation/drug effects , Drug Design , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Quinolines/chemistry , Aminoquinolines/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , DNA (Cytosine-5-)-Methyltransferase 1 , DNA (Cytosine-5-)-Methyltransferases/antagonists & inhibitors , DNA (Cytosine-5-)-Methyltransferases/metabolism , DNA Methyltransferase 3A , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Pyrimidines/chemistry , Structure-Activity Relationship
9.
Org Lett ; 15(18): 4734-7, 2013 Sep 20.
Article in English | MEDLINE | ID: mdl-24001374

ABSTRACT

Synthetic studies on hemicalide, a recently isolated marine natural product displaying highly potent antiproliferative activity and a unique mode of action, have highlighted a reliable Horner-Wadsworth-Emmons olefination to create the C6-C7 alkene and a remarkable efficient Suzuki-Miyaura coupling to form the C15-C16 bond, resulting in the development of a convergent approach toward the C1-C25 fragment.


Subject(s)
Alkenes/chemistry , Antineoplastic Agents/chemical synthesis , Biological Products/chemical synthesis , Polyketides/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Biological Products/chemistry , Biological Products/pharmacology , Marine Biology , Molecular Structure , Polyketides/chemistry , Polyketides/pharmacology , Porifera/chemistry , Stereoisomerism
10.
Phytochemistry ; 94: 184-91, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23618620

ABSTRACT

Six dichapetalins named dichapetalins N-S were isolated from Dichapetalum mombuttense, Dichapetalum zenkeri and Dichapetalum leucosia. They were accompanied in the same plants by the known dichapetalins A, B, C, I, L and M. The structures of the compounds were elucidated by 1D and 2D NMR experiments and mass spectrometry. They all possessed the dammarane skeleton substituted at position C-3 by a C6-C2 unit forming a 2-phenylpyran moiety. All contained a lactone ring in the side chain except dichapetalins O, Q and R, in which this ring was replaced by a lactol. Dichapetalin Q and R were also the first dichapetalins bearing a tertiary methyl and a double bond instead of the cyclopropane of the dammaranes. All these compounds were assayed against cancer cell lines HCT116 and WM 266-4 and displayed cytotoxic and anti-proliferative activities in the 10(-6) to 10(-8)M range.


Subject(s)
Antineoplastic Agents, Phytogenic/chemistry , Magnoliopsida/chemistry , Plant Extracts/chemistry , Plant Roots/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Antineoplastic Agents, Phytogenic/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , HCT116 Cells , HL-60 Cells , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Magnetic Resonance Spectroscopy/methods , Magnoliopsida/classification , Molecular Structure , Plant Extracts/isolation & purification , Plant Extracts/pharmacology , Species Specificity , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity Relationship
11.
J Org Chem ; 78(3): 855-64, 2013 Feb 01.
Article in English | MEDLINE | ID: mdl-23301639

ABSTRACT

Hemicalide is a novel marine metabolite polyketide distinguished by a unique mechanism of action. Because of insufficient quantities of purified material, this natural product has evaded complete stereochemical assignments. Recently, we have determined the relative stereochemistry of the C8-C13 hexad by synthesizing the C1-C13 fragment. Presently, we report the assignment of the C17-C25 δ-lactone fragment. NMR analysis of authentic hemicalide along with a computational conformation study allowed us to reduce the number of putative relative isomers from 16 to 4. Concise syntheses of the four candidate diastereomers were achieved using a common strategy based on a Dias aldehyde allylation reaction, an intramolecular Horner-Wadsworth-Emmons olefination, and a dihydroxylation reaction. Finally, thorough NMR comparisons enabled us to deduce the relative stereochemistry of the C1-C17 fragment with high certainty.


Subject(s)
Lactones/chemical synthesis , Macrolides/chemical synthesis , Polyketides/chemical synthesis , Lactones/chemistry , Macrolides/chemistry , Magnetic Resonance Spectroscopy , Molecular Conformation , Polyketides/chemistry , Stereoisomerism
12.
J Nat Prod ; 75(1): 34-47, 2012 Jan 27.
Article in English | MEDLINE | ID: mdl-22168134

ABSTRACT

Thirty new cycloartane derivatives (1-3, 5-12, 14-32) have been isolated from the leaves of Neoboutonia melleri. Their novelty stems from the loss of one of the C-4 methyl groups (1-3, 5-12, 14-25, and 32) and from the presence of an "extra" carbon atom in the side chain (1-3, 5-12, 14-20, 26-29, and 30-32). Furthermore, compound 32 possesses a rare triterpene skeleton with the cyclopropane ring fused onto C-1 and C-10, instead of C-9 and C-10. The structures were determined by spectrometric means, chemical correlations, and X-ray crystallography of derivative 1c. The substitution pattern in ring A, with a cyclopropyl ring conjugated with an α,ß-unsaturated carbonyl moiety, confers to the molecule a particular reactivity, giving rise to a formal inversion of the stereochemistry of the cyclopropane ring under UV irradiation. These compounds showed an interesting level of activity on the proteasome pathway, thus motivating their evaluation as possible anticancer agents. The large number of isolated compounds permitted a structure-activity relationship analysis, which showed that the presence of the two enone functions was a requirement for the activity.


Subject(s)
Euphorbiaceae/chemistry , Proteasome Inhibitors , Triterpenes/isolation & purification , Triterpenes/pharmacology , Cameroon , Molecular Structure , Plant Leaves/chemistry , Plant Stems/chemistry , Structure-Activity Relationship , Triterpenes/chemistry
13.
Bioorg Med Chem ; 20(2): 819-31, 2012 Jan 15.
Article in English | MEDLINE | ID: mdl-22206869

ABSTRACT

The interesting pharmacological properties of neoboutomellerones 1 and 2 were the basis for the assembly of a small library of analogues consisting of natural products isolated from the plant Neoboutonia melleri and of semisynthetic derivatives. As the two enone systems (C23-C24a and C1-C3) and the two hydroxyls groups (C22 and C26) of neoboutomellerones are required for activity, modifications were focused on these functional groups. Biological evaluation by using a cellular assay for proteasome activity provided clues regarding the mechanism of action of these natural products and synthetic derivatives. Certain neoboutomellerone derivatives inhibited the proliferation of human WM-266-4 melanoma tumor cells at submicromolar concentration and warrant evaluation as anticancer agents.


Subject(s)
Antineoplastic Agents/chemical synthesis , Biological Products/chemistry , Proteasome Inhibitors , Triterpenes/chemical synthesis , Ubiquitin/antagonists & inhibitors , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Cell Line, Tumor , Euphorbiaceae/chemistry , Humans , Proteasome Endopeptidase Complex/metabolism , Signal Transduction/drug effects , Triterpenes/chemistry , Triterpenes/toxicity , Ubiquitin/metabolism
14.
Planta Med ; 77(14): 1605-9, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21425033

ABSTRACT

Six carvotanacetone derivatives (1- 6), amongst which four new compounds (1- 4), were isolated from the aerial parts of Sphaeranthus ukambensis Vatke & O. Hoffm. The structures of the molecules were elucidated by complementary spectroscopic methods, and their biological properties were investigated using human DLD-1 colon cancer cells engineered to stably express a 4 ubiquitin-luciferase (4 Ub-Luc) reporter protein. Five of the isolated carvotanacetone derivatives (2- 6) were found to inhibit the proliferation of the colon cancer cells and interfere with the ubiquitin-proteasome pathway, with potencies in a micromolar range.


Subject(s)
Asteraceae/chemistry , Plant Extracts/chemistry , Protease Inhibitors/pharmacology , Proteasome Endopeptidase Complex/metabolism , Terpenes/pharmacology , Ubiquitin/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Kenya , Plant Components, Aerial/chemistry , Terpenes/chemistry , Terpenes/isolation & purification
15.
J Org Chem ; 74(18): 7034-45, 2009 Sep 18.
Article in English | MEDLINE | ID: mdl-19694414

ABSTRACT

The challenging determination of the relative stereochemistry of a complex natural polyketide portion was achieved. After careful NMR analysis, a concise synthesis of a set of possible relative diastereomers (only 6 diastereomers out of the 32 initially envisioned) has been carried out using a common strategy based on enantioselective aldol reactions. With a high predictability, final NMR comparison established the relative stereochemistry of the C1-C17 fragment of this natural product.


Subject(s)
Biological Products , Macrolides , Biological Products/chemical synthesis , Biological Products/chemistry , Macrolides/chemical synthesis , Macrolides/chemistry , Magnetic Resonance Spectroscopy , Stereoisomerism
16.
Naunyn Schmiedebergs Arch Pharmacol ; 375(4): 241-50, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17453175

ABSTRACT

F15063 (N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine fumarate salt) is a novel potential antipsychotic with dopamine D(2)/D(3) blocking properties and agonist activity at 5-HT(1A) and D(4) receptors. The pertinent parameter for pharmacological activity of antipsychotics appears to be central D2-like receptor occupancy. However, its duration is not necessarily correlated with drug plasma levels, on which clinical dosing regimens are often based. Thus, we compared in mice the duration of actions of F15063 and haloperidol to (1) inhibit apomorphine-induced climbing and sniffing (behavioural measures of D2-like receptor antagonism) and (2) occupy D2-like receptors in vivo in the striatum and olfactory tubercles (inhibition of [(3)H]nemonapride binding). Finally, we measured plasma levels of F15063. D2-like receptor occupancy in the striatum remained elevated at 1, 4 and 8 h postadministration, with both F15063 (ID(50): 7.1, 3.6 and 16.5 mg/kg p.o., respectively) and the typical antipsychotic, haloperidol (ID(50): 1.4, 0.52 and 0.53 mg/kg p.o., respectively). This was paralleled by a protracted inhibition of apomorphine-induced climbing (ED(50): 0.9, 2.8 and 3.6 mg/kg p.o., and 0.21, 0.37 and 0.87 mg/kg p.o., respectively, for F15063 and haloperidol). In contrast, after administration of 10 mg/kg p.o. of F15063, its plasma levels decreased rapidly: 15.2, 2.1 and 0.6 ng/ml, 1, 4 and 8 h after administration, respectively. A similar pattern of results was observed when F15063 and haloperidol were administered i.p. and s.c., respectively. To summarise, the time-course of D2-like receptor occupancy and inhibition of apomorphine-climbing (and sniffing) behaviours was similarly long lasting with F15063 and haloperidol. In addition, the durations of action of F15063 and haloperidol in a behavioural model of antipsychotic-like activity were closely correlated to their occupancy of central D2-like receptors, and much longer than their presence in plasma.


Subject(s)
Antipsychotic Agents/pharmacology , Benzofurans/pharmacology , Benzylamines/pharmacology , Cyclopentanes/pharmacology , Dopamine Antagonists/pharmacology , Dopamine D2 Receptor Antagonists , Receptors, Dopamine D3/antagonists & inhibitors , Receptors, Dopamine D4/agonists , Serotonin 5-HT1 Receptor Agonists , Serotonin Receptor Agonists/pharmacology , Animals , Antipsychotic Agents/blood , Apomorphine/pharmacology , Benzamides/metabolism , Benzofurans/blood , Benzylamines/blood , Cyclopentanes/blood , Haloperidol/pharmacology , Male , Mice
17.
Fundam Clin Pharmacol ; 19(5): 545-53, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16176333

ABSTRACT

Vinorelbine (VRL) (IV Navelbine) is a semi-synthetic vinca alkaloid, used in therapeutics for the treatment of non-small-cell lung cancer and advanced breast cancer. The aim of this study was to characterize the cytochrome P450 (CYP) isoenzymes involved in VRL metabolism. VRL was incubated at 1.28 x 10(-5) m for 90 min with human hepatic microsomes prepared from 14 donors (one woman and 13 men aged from 27 to 76 years old) and characterized for CYP1A2, CYP2D6, CYP2E1 and CYP3A4 activities. A four-combined-approach study was performed, including correlation between CYP activities and VRL metabolism among the 14 batches of microsomes, inhibition of VRL biotransformation by isoform-selective substrates and by specific inhibitory antibodies, and incubation with supersomes. Analysis of unchanged VRL and its metabolites was performed using an HPLC method coupled with both radioactive and UV detections. No correlation between CYP1A2 or CYP2E1 and VRL metabolism was observed in the 14 batches of microsomes used. A correlation was shown between VRL metabolism and CYP3A4 activity as determined with the dextromethorphan N-demethylase and nifedipine oxidase activities (r(2)=0.80 and 0.59, respectively). These results were strengthened by a correlation between the metabolism extent of VRL and CYP3A4 protein content determined by immunoblotting (r(2)=0.75). Furthermore, VRL biotransformation was inhibited by troleandomycine, the CYP3A4-specific inhibitor substrate (80% of inhibition) and by anti-CYP3A antibodies (36% of inhibition). On the contrary, a low correlation with CYP2D6 activity as determined by dextrometorphan O-demethylation (r(2)=0.31) was established. CYP2D6 supersomes did not metabolize the drug whereas 63.4% of VRL were metabolized by microsomes overexpressing CYP3A4 isoform. These data indicated that CYP3A4 is the main enzyme involved in the hepatic metabolism of VRL in human, whereas CYP2D6 is not involved.


Subject(s)
Cytochrome P-450 CYP2D6/metabolism , Cytochrome P-450 Enzyme System/metabolism , Vinblastine/analogs & derivatives , Adult , Aged , Animals , Antibodies/pharmacology , Antineoplastic Agents, Phytogenic/metabolism , Blotting, Western , Cytochrome P-450 CYP2D6/immunology , Cytochrome P-450 CYP2D6 Inhibitors , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/immunology , Enzyme Inhibitors/pharmacology , Female , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/immunology , Isoenzymes/metabolism , Ketoconazole/pharmacology , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Middle Aged , Time Factors , Tritium , Troleandomycin/pharmacology , Vinblastine/metabolism , Vinorelbine
18.
J Pharmacol Exp Ther ; 312(3): 1034-42, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15528450

ABSTRACT

The aim of the present study was to establish the relationship between the plasma and brain concentration-time profiles of F 13640 [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl}piperidin-1-yl]methanone, fumaric acid salt] after acute administration and both its hyper- and hypoanalgesic effects in rats. The maximal plasma concentration (C(max)) of F 13640 after i.p. administration of 0.63 mg/kg was obtained at 15 min and decreased to half its maximal value after about 1 h. The amount of F 13640 collected by means of in vivo microdialysis in hippocampal dialysates could be measured reliably after 0.63 and 2.5 mg/kg, reached its maximum at about 1 h, and fell to half of its maximal value at about 3 h. 5-Hydroxytryptamine 1A (5-HT(1A)) receptor occupancy was estimated by ex vivo binding in rat brain sections. F 13640 inhibited [(3)H]8-hydroxy-2-[di-n-propylamino] tetralin binding ex vivo in rat hippocampus, entorhinal cortex, and frontal cortex (ED(50), 0.34 mg/kg i.p.). Maximal inhibition was reached at approximately 30 min after 0.63 mg/kg F 13640 and fell to half of its value after about 4 to 8 h. After injection (15 min) in the paw pressure test, F 13640 (0.63 mg/kg i.p.) induced an initial hyperalgesia that was followed 4 h later by a paradoxical analgesia that lasted until 8 h. In contrast, in the formalin test, F 13640 inhibited pain behaviors until 4 h after drug administration. F 13640 also produced elements of the 5-HT syndrome that lasted up to 4 h after administration. These results demonstrate that F 13640 induces hyperalgesia and/or analgesia with a time course that parallels the occupancy of 5-HT(1A) receptors and the presence of the compound in blood and brain.


Subject(s)
Analgesics/pharmacology , Hyperalgesia/chemically induced , Piperidines/pharmacology , Pyridines/pharmacology , Serotonin 5-HT1 Receptor Agonists , Serotonin Receptor Agonists/pharmacology , Animals , Dose-Response Relationship, Drug , Male , Microdialysis , Piperidines/blood , Pyridines/blood , Rats , Rats, Sprague-Dawley
19.
Eur J Pharmacol ; 497(1): 29-33, 2004 Aug 16.
Article in English | MEDLINE | ID: mdl-15321732

ABSTRACT

The selective, high-efficacy 5-HT(1A) receptor agonist, (3-chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl]piperidin-1-yl]-methanone (F 13640) has been reported to produce long-term analgesia in rodent models of chronic nociceptive and neuropathic pain; it also preempts allodynia following spinal cord injury. Here, rats underwent spinal cord injury, fully developed allodynia, and were infused with saline or 0.63 mg/day of F 13640 for 56 days. Infusion was then discontinued, and further assessments of allodynia (vocalization threshold to von Frey filament stimulation, responses to brush and cold) were conducted for another 70 days. F 13640-induced analgesia persisted during this post-treatment period. The data offer initial evidence that high-efficacy 5-HT(1A) receptor activation produces an unprecedented curative-like action on pathological pain.


Subject(s)
Analgesics/therapeutic use , Pain/drug therapy , Piperidines/therapeutic use , Pyridines/therapeutic use , Serotonin 5-HT1 Receptor Agonists , Spinal Cord Injuries/complications , Analgesics/pharmacology , Animals , Behavior, Animal/drug effects , Cold Temperature , Female , Infusions, Intravenous , Pain/etiology , Pain Measurement , Pain Threshold , Piperidines/pharmacology , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Touch , Vocalization, Animal/drug effects
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