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1.
ChemMedChem ; 17(9): e202100653, 2022 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-35018729

RESUMEN

STAG2 (SA2) is a critical component of the cohesin complex that regulates gene expression and the separation of sister chromatids in cells. Mutations in STAG2 have been identified in over thirty different types of cancers including myeloid leukaemia, non-small cell lung, bladder and Ewing sarcoma. Selectively inhibiting cancer cells lacking of STAG2 is an attractive approach for the cancer therapy. Here we report that a small molecule, StagX1, identified through a high-throughput screening, inhibits the growth of Ewing sarcoma cells possessing mutant STAG2. A new synthetic route to the StagX1 scaffold and new versions of the molecule along with their activity in a cell viability assay are reported.


Asunto(s)
Sarcoma de Ewing , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Humanos , Mutación , Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/genética
2.
Org Lett ; 23(8): 2911-2914, 2021 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-33783221

RESUMEN

A diastereoselective [4 + 2] cycloisomerization of asymmetric allenyl dienes is reported. The asymmetric dienyl allenes are synthesized using the method reported by Ma. These substrates readily undergo diastereoselective intramolecular rhodium catalyzed [4 + 2] cycloisomerization analogous to thermal intramolecular Diels-Alder reactions. Overall, 29 examples are presented with tethers possessing nitrogen, oxygen, and carbon. Diastereoselectivities range from 99:1 to 90:10 in most examples.

3.
ACS Chem Biol ; 15(11): 2916-2928, 2020 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-33074669

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer. PDACs harbor oncogenic mutations in the KRAS gene, and ongoing efforts to directly target its mutant protein product to inhibit tumor growth are a priority not only in pancreatic cancer but in other malignancies such as lung and colorectal cancers where KRAS is also commonly mutated. An alternative strategy to directly targeting KRAS is to identify and target druggable receptors involved in dysregulated cancer hallmarks downstream of KRAS dysregulation. Liver X receptors (LXRs) are members of the nuclear receptor family of ligand-modulated transcription factors and are involved in the regulation of genes which function in key cancer-related processes, including cholesterol transport, lipid and glucose metabolism, and inflammatory and immune responses. Modulation of LXRs via small molecule ligands has emerged as a promising approach for directly targeting tumor cells or the stromal and immune cells within the tumor microenvironment. We have previously shown that only one of the two LXR subtypes (LXRß) is expressed in pancreatic cancer cells, and targeting LXR with available synthetic ligands blocked the proliferation of PDAC cells and tumor formation. In a screen of a focused library of drug-like small molecules predicted to dock in the ligand-binding pocket of LXRß, we identified two novel LXR ligands with more potent antitumor activity than current LXR agonists used in our published studies. Characterization of the two lead compounds (GAC0001E5 and GAC0003A4) indicates that they function as LXR inverse agonists which inhibit their transcriptional activity. Prolonged treatments with novel ligands further revealed their function as LXR "degraders" which significantly reduced LXR protein levels in all three PDAC cell lines tested. These findings support the utility of these novel inhibitors in basic research on ligand design, allosteric mechanisms, and LXR functions and their potential application as treatments for advanced pancreatic cancer and other recalcitrant malignancies.


Asunto(s)
Antineoplásicos/farmacología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Receptores X del Hígado/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/farmacología , Antineoplásicos/química , Carcinoma Ductal Pancreático/metabolismo , Línea Celular Tumoral , Agonismo Inverso de Drogas , Humanos , Ligandos , Receptores X del Hígado/agonistas , Neoplasias Pancreáticas/metabolismo , Proteolisis/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/química
4.
Chem Commun (Camb) ; 56(14): 2211-2213, 2020 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-32039415

RESUMEN

Correction for 'Diastereoselective synthesis of 1,3-disubstituted isoindolines and sultams via bronsted acid catalysis' by Ye Tao et al., Chem. Commun., 2018, 54, 11292-11295.

5.
Biochem Pharmacol ; 174: 113808, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31930961

RESUMEN

Separase, a sister chromatid cohesion-resolving enzyme, is an oncogene and overexpressed in many human cancers. Sepin-1 (2,2-dimethyl-5-nitro-2H-benzimidazole-1,3-dioxide) is a potent separase inhibitor that impedes cancer cell growth, cell migration, and wound healing, suggesting that Sepin-1 possesses a great potential to target separase-overexpressing tumors. As a part of the IND-enabling studies to bring Sepin-1 to clinic, herein we report the results from a 28-day repeat-dose pharmacokinetic study of Sepin-1 in rats. Sepin-1 was intravenously administered to Sprague-Dawley rats once daily for 28 days at three different (5, 10, and 20 mg/kg) doses. Blood samples were collected after administration of doses on days 1 and 28. Sepin-1 is unstable and isomerizes in basic solutions, but it is stable in acidic buffer such as citrate-buffered saline (pH 4.0). UHPLC-MS analysis indicated Sepin-1 was rapidly metabolized in vivo. One of the major metabolites was an amine adduct of 2,2-dimethyl-5-nitro-2H-benzimidazole (named Sepin-1.55). The concentration of Sepin-1.55 in blood samples was Sepin-1 dose-dependent and used for pharmacokinetic analysis of Sepin-1. Tmax was approximately 5-15 min. The data suggest that no Sepin-1 accumulation occurred from daily repeat dosing and similar exposures on the first and final day of dosing. Data also suggest a gender difference, namely that female rats have more exposure and slower clearance than male rats. The data support that Sepin-1 is a potential drug candidate that can be further developed to treat Separase-overexpressing human tumors.


Asunto(s)
Bencimidazoles , Inhibidores de Cisteína Proteinasa , Separasa/antagonistas & inhibidores , Animales , Bencimidazoles/química , Bencimidazoles/farmacocinética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacocinética , Estabilidad de Medicamentos , Femenino , Masculino , Ratas , Ratas Sprague-Dawley , Separasa/sangre
6.
Front Pharmacol ; 10: 907, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31507411

RESUMEN

Hypofunction of the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) has been implicated in a variety of disorders including substance use disorders. As such, approaches to enhance 5-HT2CR signaling display therapeutic potential. In the present study, we show that disruption of the 5-HT2CR interaction with the protein phosphatase and tensin homolog (PTEN) via peptidomimetics enhances 5-HT2CR-mediating signaling in vitro and potentiates selective 5-HT2CR agonists in behavioral rodent models. Overall, the present study provides further evidence that 5-HT2CR activity can be modulated through an allosteric protein-protein interaction. This work provides the groundwork for the continued exploration of protein-protein interactions that can allosterically modulate this critical receptor and other important G protein-coupled receptors (GPCRs) for new therapeutic development through mechanisms that may display clinical utility.

8.
Chem Commun (Camb) ; 54(80): 11292-11295, 2018 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-30232479

RESUMEN

The bis(trifluoromethane)sulfonimide (Tf2NH) catalyzed intramolecular hydroamidation of terminal alkynes is reported. The combination of Et3SiH and Tf2NH provides cis-1,3-disubstituted isoindolines and sultams in high yield (up to 98%) and high diastereoselectivity (up to 99 : 1 d.r.).

9.
PLoS One ; 13(8): e0203137, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30157263

RESUMEN

The serotonin (5-HT) 5-HT2A receptor (5-HT2AR) and 5-HT2C receptor (5-HT2CR) in the central nervous system are implicated in a range of normal behaviors (e.g., appetite, sleep) and physiological functions (e.g., endocrine secretion) while dysfunctional 5-HT2AR and/or 5-HT2CR are implicated in neuropsychiatric disorders (e.g., addiction, obesity, schizophrenia). Preclinical studies suggest that the 5-HT2AR and 5-HT2CR may act in concert to regulate the neural bases for behavior. Here, we utilize three distinct biophysical and immunocytochemistry-based approaches to identify and study this receptor complex in cultured cells. Employing a split luciferase complementation assay (LCA), we demonstrated that formation of the 5-HT2AR:5-HT2CR complex exists within 50 nm, increases proportionally to the 5-HT2CR:5-HT2AR protein expression ratio, and is specific to the receptor interaction and not due to random complementation of the luciferase fragments. Using a proximity ligation assay (PLA), we found that cells stably expressing both the 5-HT2AR and 5-HT2CR exhibit 5-HT2AR:5-HT2CR heteroreceptor complexes within 40 nm of each other. Lastly, bioluminescence resonance energy transfer (BRET) analyses indicates the formation of a specific and saturable 5-HT2AR:5-HT2CR interaction, suggesting that the 5-HT2AR and 5-HT2CR form a close interaction within 10 nm of each other in intact live cells. The bioengineered receptors generated for the LCA and the BRET exhibit 5-HT-mediated intracellular calcium signaling as seen for the native receptors. Taken together, this study validates a very close 5-HT2AR:5-HT2CR interaction in cultured cells.


Asunto(s)
Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2C/metabolismo , Animales , Fenómenos Biofísicos , Células CHO , Calcio/metabolismo , Señalización del Calcio/fisiología , Cricetulus , Células HEK293 , Humanos , Receptor de Serotonina 5-HT2A/genética , Receptor de Serotonina 5-HT2C/genética , Serotonina/metabolismo , Transfección
10.
Front Pharmacol ; 9: 313, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29867452

RESUMEN

Separase, a known oncogene, is widely overexpressed in numerous human tumors of breast, bone, brain, blood, and prostate. Separase is an emerging target for cancer therapy, and separase enzymatic inhibitors such as sepin-1 are currently being developed to treat separase-overexpressed tumors. Drug metabolism plays a critical role in the efficacy and safety of drug development, as well as possible drug-drug interactions. In this study, we investigated the in vitro metabolism of sepin-1 in human, mouse, and rat liver microsomes (RLM) using metabolomic approaches. In human liver microsomes (HLM), we identified seven metabolites including one cysteine-sepin-1 adduct and one glutathione-sepin-1 adduct. All the sepin-1 metabolites in HLM were also found in both mouse and RLM. Using recombinant CYP450 isoenzymes, we demonstrated that multiple enzymes contributed to the metabolism of sepin-1, including CYP2D6 and CYP3A4 as the major metabolizing enzymes. Inhibitory effects of sepin-1 on seven major CYP450s were also evaluated using the corresponding substrates recommended by the US Food and Drug Administration. Our studies indicated that sepin-1 moderately inhibits CYP1A2, CYP2C19, and CYP3A4 with IC50 < 10 µM but weakly inhibits CYP2B6, CYP2C8/9, and CYP2D6 with IC50 > 10 µM. This information can be used to optimize the structures of sepin-1 for more suitable pharmacological properties and to predict the possible sepin-1 interactions with other chemotherapeutic drugs.

11.
Bioorg Med Chem Lett ; 28(8): 1381-1385, 2018 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-29555153

RESUMEN

The approach of tethering together two known receptor ligands, to be used as molecular probes for the study of G protein-coupled receptor (GPCR) systems, has proven to be a valuable approach. Selective ligands that possess functionality that can be used to link to other ligands, are useful in the development of novel antagonists and agonists. Such molecules can also be attached to reporter molecules, such as fluorophores, for the study of GPCR dimerization and its role in signaling. The highly selective serotonin (5-HT) 5-HT2A receptor (5-HT2AR) antagonist M100907 (volinanserin) is of clinical interest in the treatment of neurological and mental health disorders. Here, we synthesized the most active (+)-M100907 enantiomer as well as a series of derivatives that possessed either an alkyne or an azide. The triazole resulting from the dipolar cycloaddition of these groups did not interfere with the ability of the bivalent ligand to act as an antagonist. Thus, we have synthesized a number of compounds which will prove useful in elucidating the role of the 5-HT2AR in the central nervous system.


Asunto(s)
Fluorobencenos/farmacología , Piperidinas/farmacología , Receptor de Serotonina 5-HT2A/metabolismo , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Alquinos/síntesis química , Alquinos/química , Alquinos/farmacología , Animales , Azidas/síntesis química , Azidas/química , Azidas/farmacología , Células CHO , Calcio/metabolismo , Cricetulus , Fluorobencenos/síntesis química , Fluorobencenos/química , Piperidinas/síntesis química , Piperidinas/química , Antagonistas del Receptor de Serotonina 5-HT2/síntesis química , Antagonistas del Receptor de Serotonina 5-HT2/química , Estereoisomerismo
12.
ACS Chem Neurosci ; 9(3): 514-521, 2018 03 21.
Artículo en Inglés | MEDLINE | ID: mdl-29111677

RESUMEN

The 5-HT2A receptor (5-HT2AR) plays an important role in various neuropsychiatric disorders, including substance use disorder and schizophrenia. Homodimerization of this receptor has been suggested, but tools that allow direct assessment of the relevance of the 5-HT2AR:5-HT2AR homodimer in these disorders are necessary. We chemically modified the selective 5-HT2AR antagonist M100907 to synthesize a series of homobivalent ligands connected by ethylene glycol linkers of varying lengths that may be useful tools for probing 5-HT2AR:5-HT2AR homodimer function. We tested these molecules for 5-HT2AR antagonist activity in a cell line stably expressing the functional 5-HT2AR and quantified a downstream signaling target, activation (phosphorylation) of extracellular regulated kinases 1/2 (ERK1/2), in comparison to in vivo efficacy of altering spontaneous or cocaine-evoked locomotor activity in rats. All of the synthetic compounds inhibited 5-HT-mediated phosphorylation of ERK1/2 in the cellular signaling assay; the potency of the bivalent ligands varied as a function of linker length, with the intermediate linker lengths being the most potent. The Ki values for the binding of bivalent ligands to 5-HT2AR were only slightly lower than the values for the parent (+)-M100907 compound, but significant selectivity for 5-HT2AR over 5-HT2BR or 5-HT2CR binding was retained. In addition, the 11-atom-linked bivalent 5-HT2AR antagonist (2 mg/kg, intraperitoneally) demonstrated efficacy on par with that of (+)-M100907 in inhibiting cocaine-evoked hyperactivity. As we develop further strategies for ligand-evoked receptor assembly and analyses of diverse signaling and functional roles, these novel homobivalent 5-HT2AR antagonist ligands will serve as useful in vitro and in vivo probes of 5-HT2AR structure and function.


Asunto(s)
Calcio/metabolismo , Cocaína/farmacología , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Fosforilación/efectos de los fármacos , Unión Proteica/efectos de los fármacos , Receptor de Serotonina 5-HT2A/metabolismo , Transducción de Señal/efectos de los fármacos
13.
ACS Chem Neurosci ; 8(5): 1004-1010, 2017 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-28414422

RESUMEN

The development of probe molecules that can be used to investigate G protein-coupled receptor (GPCR) pharmacology, trafficking, and relationship with other GPCRs is an important and growing area of research. Here, we report the synthesis of analogues of the known selective serotonin (5-HT) 5-HT2C receptor (5-HT2CR) agonist WAY163909 which were designed to allow for the attachment of a second ligand, signaling or reporter molecules, as well as immobilization agents to the parent molecule with the maintenance of agonist activity. This goal was accomplished by the synthesis of novel molecules in which sites a-d were modified and resulting compounds were analyzed pharmacologically in vitro.


Asunto(s)
Azepinas/farmacología , Indoles/farmacología , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Animales , Calcio/metabolismo , Línea Celular , Humanos
14.
Bioorg Med Chem Lett ; 26(18): 4446-4450, 2016 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-27530289

RESUMEN

Due to the oncogenic activity of cohesin protease, separase in human cancer cells, modulation of separase enzymatic activity could constitute a new therapeutic strategy for targeting resistant, separase-overexpressing aneuploid tumors. Herein, we report the synthesis, structural information, and structure-activity relationship (SAR) of separase inhibitors based on modification of the lead molecule 2,2-dimethyl-5-nitro-2H-benzimidazole-1,3-dioxide, named Sepin-1, (1) identified from a high-throughput-screen. Replacement of -NO2 at C5 with other functional groups reduce the inhibitory activity in separase enzymatic assay. Substitution of the two methyl groups with other alkyl chains at the C2 moderately improves the effects on the inhibitory activity of those compounds. Modifications on 2H-benzimidazole-1,3-dioxide or the skeleton have variable effect on inhibition of separase enzymatic activity. Density-functional theory (DFT) calculations suggest there may be a correlation between the charges on the oxide moieties on these compounds and their activity in inhibiting separase enzyme.


Asunto(s)
Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Inhibidores Enzimáticos/farmacología , Separasa/antagonistas & inhibidores , Bencimidazoles/química , Inhibidores Enzimáticos/química , Relación Estructura-Actividad
15.
Org Lett ; 17(16): 3972-4, 2015 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-26258884

RESUMEN

Dysiherbaine, a natural product isolated from the Marine sponge Dysidea herbacea, has been shown to be a selective agonist of non-NMDA type glutamate receptors, kainate receptors. An enantioselective synthesis of dysiherbaine is reported. Metathesis of the diene followed by conversion of the resulting alkene to the amino alcohol and addition of the amino acid provides the natural product. This synthesis differs from previous approaches to the molecule in that the functionality on the tetrahydropyran ring is installed late in the route.


Asunto(s)
Alanina/análogos & derivados , Productos Biológicos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Poríferos/química , Receptores de Ácido Kaínico/efectos de los fármacos , Alanina/síntesis química , Alanina/química , Alanina/farmacología , Alquenos/química , Aminoácidos/química , Animales , Productos Biológicos/química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Biología Marina , Estructura Molecular , Receptores de Glutamato/efectos de los fármacos , Estereoisomerismo
16.
Chem Commun (Camb) ; 50(39): 5007-10, 2014 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-24706156

RESUMEN

A rhodium-BozPHOS based complex is reported. This complex is competent in catalyzing the [4+2+2] cycloisomerization of cyclooctatrienes in moderate to good yields. The X-ray crystal structure of this complex is reported, along with formation of both bicyclic and tricyclic cyclooctatrienes.

17.
Org Lett ; 16(4): 1033-5, 2014 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-24495075

RESUMEN

The synthesis of proline-based N-heterocyclic carbene ligands is reported. An approach to a variety of proline-containing imidazolium NHC precursors is presented. The proline amino acids are shown to be compatible with peptide synthetic methods by incorporation into tripeptides. Following peptide synthesis, the carbene is generated and bound to rhodium.


Asunto(s)
Metano/análogos & derivados , Prolina/química , Rodio/química , Catálisis , Imidazoles/química , Ligandos , Metano/síntesis química , Metano/química , Estructura Molecular , Estereoisomerismo
18.
ACS Comb Sci ; 15(7): 340-3, 2013 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-23742807

RESUMEN

Through the use of the dipolar cycloaddition of isomunchones with olefins the 2(1H)-pyridone ring system has been synthesized. (1) The use of different cyclization partners followed by diversification of the initial scaffold has provided libraries of 4-hydroxy-2(1H)-pyridones. There are no examples of this ring system in either PubChem or the MLSMR.


Asunto(s)
Piridonas/síntesis química , Rodio/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Catálisis , Ciclización , Piridonas/química , Bibliotecas de Moléculas Pequeñas/química
19.
J Neurosci ; 33(4): 1615-30, 2013 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-23345234

RESUMEN

Serotonin (5-hydroxytryptamine; 5-HT) signaling through the 5-HT(2C) receptor (5-HT(2C)R) is essential in normal physiology, whereas aberrant 5-HT(2C)R function is thought to contribute to the pathogenesis of multiple neural disorders. The 5-HT(2C)R interacts with specific protein partners, but the impact of such interactions on 5-HT(2C)R function is poorly understood. Here, we report convergent cellular and behavioral data that the interaction between the 5-HT(2C)R and protein phosphatase and tensin homolog (PTEN) serves as a regulatory mechanism to control 5-HT(2C)R-mediated biology but not that of the closely homologous 5-HT(2A)R. A peptide derived from the third intracellular loop of the human 5-HT(2C)R [3L4F (third loop, fourth fragment)] disrupted the association, allosterically augmented 5-HT(2C)R-mediated signaling in live cells, and acted as a positive allosteric modulator in rats in vivo. We identified the critical residues within an 8 aa fragment of the 3L4F peptide that maintained efficacy (within the picomolar range) in live cells similar to that of the 3L4F peptide. Last, molecular modeling identified key structural features and potential interaction sites of the active 3L4F peptides against PTEN. These compelling data demonstrate the specificity and importance of this protein assembly in cellular events and behaviors mediated by 5-HT(2C)R signaling and provide a chemical guidepost to the future development of drug-like peptide or small-molecule inhibitors as neuroprobes to study 5-HT(2C)R allostery and therapeutics for 5-HT(2C)R-mediated disorders.


Asunto(s)
Modelos Moleculares , Fosfohidrolasa PTEN/química , Fosfohidrolasa PTEN/metabolismo , Receptor de Serotonina 5-HT2C/química , Receptor de Serotonina 5-HT2C/metabolismo , Transducción de Señal/fisiología , Secuencia de Aminoácidos , Animales , Humanos , Immunoblotting , Inmunoprecipitación , Masculino , Datos de Secuencia Molecular , Actividad Motora/fisiología , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismo , Transfección
20.
ACS Chem Neurosci ; 4(1): 110-21, 2013 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-23336050

RESUMEN

Relapse to cocaine dependence, even after extended abstinence, involves a number of liability factors including impulsivity (predisposition toward rapid, unplanned reactions to stimuli without regard to negative consequences) and cue reactivity (sensitivity to cues associated with cocaine-taking which can promote cocaine-seeking). These factors have been mechanistically linked to serotonin (5-hydroxytryptamine, 5-HT) signaling through the 5-HT(2A) receptor (5-HT(2A)R) and 5-HT(2C)R; either a selective 5-HT(2A)R antagonist or a 5-HT(2C)R agonist suppresses impulsivity and cocaine-seeking in preclinical models. We conducted proof-of-concept analyses to evaluate whether a combination of 5-HT(2A)R antagonist plus 5-HT(2C)R agonist would have synergistic effects over these liability factors for relapse as measured in a 1-choice serial reaction time task and cocaine self-administration/reinstatement assay. Combined administration of a dose of the selective 5-HT(2A)R antagonist M100907 plus the 5-HT(2C)R agonist WAY163909, each ineffective alone, synergistically suppressed cocaine-induced hyperactivity, inherent and cocaine-evoked impulsive action, as well as cue- and cocaine-primed reinstatement of cocaine-seeking behavior. The identification of synergism between a 5-HT(2A)R antagonist plus a 5-HT(2C)R agonist to attenuate these factors important in relapse indicates the promise of a bifunctional ligand as an anti-addiction pharmacotherapeutic, setting the stage to develop new ligands with improved efficacy, potency, selectivity, and in vivo profiles over the individual molecules.


Asunto(s)
Azepinas/uso terapéutico , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Fluorobencenos/uso terapéutico , Indoles/uso terapéutico , Piperidinas/uso terapéutico , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Animales , Señales (Psicología) , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Sinergismo Farmacológico , Humanos , Hipercinesia/tratamiento farmacológico , Conducta Impulsiva/tratamiento farmacológico , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Esquema de Refuerzo , Antagonistas del Receptor de Serotonina 5-HT2/administración & dosificación
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