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1.
Free Radic Biol Med ; 204: 276-286, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37217089

RESUMO

We developed S1QEL1.719, a novel bioavailable S1QEL (suppressor of site IQ electron leak). S1QEL1.719 prevented superoxide/hydrogen peroxide production at site IQ of mitochondrial complex I in vitro. The free concentration giving half-maximal suppression (IC50) was 52 nM. Even at 50-fold higher concentrations S1QEL1.719 did not inhibit superoxide/hydrogen peroxide production from other sites. The IC50 for inhibition of complex I electron flow was 500-fold higher than the IC50 for suppression of superoxide/hydrogen peroxide production from site IQ. S1QEL1.719 was used to test the metabolic effects of suppressing superoxide/hydrogen peroxide production from site IQin vivo. C57BL/6J male mice fed a high-fat chow for one, two or eight weeks had increased body fat, decreased glucose tolerance, and increased fasting insulin concentrations, classic symptoms of metabolic syndrome. Daily prophylactic or therapeutic oral treatment of high-fat-fed animals with S1QEL1.719 decreased fat accumulation, strongly protected against decreased glucose tolerance and prevented or reversed the increase in fasting insulin level. Free exposures in plasma and liver at Cmax were 1-4 fold the IC50 for suppression of superoxide/hydrogen peroxide production at site IQ and substantially below levels that inhibit electron flow through complex I. These results show that the production of superoxide/hydrogen peroxide from mitochondrial site IQin vivo is necessary for the induction and maintenance of glucose intolerance caused by a high-fat diet in mice. They raise the possibility that oral administration of S1QELs may be beneficial in metabolic syndrome.


Assuntos
Síndrome Metabólica , Superóxidos , Camundongos , Masculino , Animais , Superóxidos/metabolismo , Peróxido de Hidrogênio/metabolismo , Peróxidos , Insulina , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL , Jejum , Tecido Adiposo/metabolismo , Glucose
2.
Bioorg Med Chem Lett ; 72: 128843, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-35688367

RESUMO

Cystic fibrosis (CF) is an autosomal recessive disease resulting from mutations on both copies of the CFTR gene. Phenylalanine deletion at position 508 of the CFTR protein (F508del-CFTR) is the most frequent mutation in CF patients. Currently, the most effective treatments of CF use a dual or triple combination of CFTR correctors and potentiators. In triple therapy, two correctors (C1 and C2) and a potentiator are employed. Herein, we describe the identification and exploration of the SAR of a series of 4-aminopyrrolidine-2-carboxylic acid C2 correctors of CFTR to be used in conjunction with our existing C1 corrector series for the treatment of CF.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Benzodioxóis , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Humanos , Mutação , Prolina/análogos & derivados , Relação Estrutura-Atividade
3.
J Pharmacol Exp Ther ; 372(1): 107-118, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31732698

RESUMO

Cystic fibrosis (CF) is the most common monogenic autosomal recessive disease in Caucasians caused by pathogenic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (CFTR). Significant small molecule therapeutic advances over the past two decades have been made to target the defective CFTR protein and enhance its function. To address the most prevalent defect of the defective CFTR protein (i.e., F508del mutation) in CF, two biomolecular activities are required, namely, correctors to increase the amount of properly folded F508delCFTR levels at the cell surface and potentiators to allow the effective opening, i.e., function of the F508delCFTR channel. Combined, these activities enhance chloride ion transport yielding improved hydration of the lung surface and subsequent restoration of mucociliary clearance. To enhance clinical benefits to CF patients, a complementary triple combination therapy consisting of two corrector molecules, type 1 (C1) and type 2, with additive mechanisms along with a potentiator are being investigated in the clinic for maximum restoration of mutated CFTR function. We report the identification and in vitro biologic characterization of ABBV-2222/GLPG2222 (4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid),-a novel, potent, and orally bioavailable C1 corrector developed by AbbVie-Galapagos and currently in clinical trials-which exhibits substantial improvements over the existing C1 correctors. This includes improvements in potency and drug-drug interaction (DDI) compared with 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (VX-809, Lumacaftor) and improvements in potency and efficacy compared with 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)indol-5-yl]cyclopropane-1-carboxamide (VX-661, Tezacaftor). ABBV-2222/GLPG2222 exhibits potent in vitro functional activity in primary patient cells harboring F508del/F508del CFTR with an EC50 value <10 nM. SIGNIFICANCE STATEMENT: To address the most prevalent defect of the defective CFTR protein (i.e., F508del mutation) in cystic fibrosis, AbbVie-Galapagos has developed ABBV-2222/GLPG2222, a novel, potent, and orally bioavailable C1 corrector of this protein. ABBV-2222/GLPG2222, which is currently in clinical trials, exhibits potent in vitro functional activity in primary patient cells harboring F508del/F508del CFTR and substantial improvements over the existing C1 correctors.


Assuntos
Benzoatos/farmacologia , Benzopiranos/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Dobramento de Proteína/efeitos dos fármacos , Animais , Sítios de Ligação , Membrana Celular/metabolismo , Células Cultivadas , Cloretos/metabolismo , Cricetinae , Regulador de Condutância Transmembrana em Fibrose Cística/química , Células HEK293 , Humanos , Moduladores de Transporte de Membrana/farmacologia , Ligação Proteica , Transporte Proteico/efeitos dos fármacos , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo
4.
ACS Med Chem Lett ; 10(11): 1543-1548, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31749908

RESUMO

Cystic fibrosis (CF) is a genetic disorder that affects multiple tissues and organs. CF is caused by mutations in the CFTR gene, resulting in insufficient or impaired cystic fibrosis transmembrane conductance regulator (CFTR) protein. The deletion of phenylalanine at position 508 of the protein (F508del-CFTR) is the most common mutation observed in CF patients. The most effective treatments of these patients employ two CFTR modulator classes, correctors and potentiators. CFTR correctors increase protein levels at the cell surface; CFTR potentiators enable the functional opening of CFTR channels at the cell surface. Triple-combination therapies utilize two distinct corrector molecules (C1 and C2) to further improve the overall efficacy. We identified the need to develop a C2 corrector series that had the potential to be used in conjunction with our existing C1 corrector series and provide robust clinical efficacy for CF patients. The identification of a pyrrolidine series of CFTR C2 correctors and the structure-activity relationship of this series is described. This work resulted in the discovery and selection of (2S,3R,4S,5S)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylic acid (ABBV/GLPG-3221), which was advanced to clinical trials.

5.
J Med Chem ; 61(4): 1436-1449, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29251932

RESUMO

Cystic fibrosis (CF) is a multiorgan disease of the lungs, sinuses, pancreas, and gastrointestinal tract that is caused by a dysfunction or deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an epithelial anion channel that regulates salt and water balance in the tissues in which it is expressed. To effectively treat the most prevalent patient population (F508del mutation), two biomolecular modulators are required: correctors to increase CFTR levels at the cell surface, and potentiators to allow the effective opening of the CFTR channel. Despite approved potentiator and potentiator/corrector combination therapies, there remains a high need to develop more potent and efficacious correctors. Herein, we disclose the discovery of a highly potent series of CFTR correctors and the structure-activity relationship (SAR) studies that guided the discovery of ABBV/GLPG-2222 (22), which is currently in clinical trials in patients harboring the F508del CFTR mutation on at least one allele.


Assuntos
Benzoatos/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Descoberta de Drogas , Amidas/síntese química , Animais , Benzoatos/síntese química , Benzoatos/farmacocinética , Cromanos/síntese química , Cães , Humanos , Proteínas Mutantes/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
6.
J Pain ; 15(4): 387.e1-14, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24374196

RESUMO

UNLABELLED: Voltage-gated Ca(2+) channels play an important role in nociceptive transmission. There is significant evidence supporting a role for N-, T- and P/Q-type Ca(2+) channels in chronic pain. Here, we report that A-1264087, a structurally novel state-dependent blocker, inhibits each of these human Ca(2+) channels with similar potency (IC50 = 1-2 µM). A-1264087 was also shown to inhibit the release of the pronociceptive calcitonin gene-related peptide from rat dorsal root ganglion neurons. Oral administration of A-1264087 produces robust antinociceptive efficacy in monoiodoacetate-induced osteoarthritic, complete Freund adjuvant-induced inflammatory, and chronic constrictive injury of sciatic nerve-induced, neuropathic pain models with ED50 values of 3.0, 5.7, and 7.8 mg/kg (95% confidence interval = 2.2-3.5, 3.7-10, and 5.5-12.8 mg/kg), respectively. Further analysis revealed that A-1264087 also suppressed nociceptive-induced p38 and extracellular signal-regulated kinase 1/2 phosphorylation, which are biochemical markers of engagement of pain circuitry in chronic pain states. Additionally, A-1264087 inhibited both spontaneous and evoked neuronal activity in the spinal cord dorsal horn in complete Freund adjuvant-inflamed rats, providing a neurophysiological basis for the observed antihyperalgesia. A-1264087 produced no alteration of body temperature or motor coordination and no learning impairment at therapeutic plasma concentrations. PERSPECTIVE: The present results demonstrate that the neuronal Ca(2+) channel blocker A-1264087 exhibits broad-spectrum efficacy through engagement of nociceptive signaling pathways in preclinical pain models in the absence of effects on psychomotor and cognitive function.


Assuntos
Analgésicos/farmacologia , Compostos Azabicíclicos/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Leucina/análogos & derivados , Neurônios/metabolismo , Nociceptividade/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Imuno-Histoquímica , Leucina/farmacologia , Masculino , Neurônios/efeitos dos fármacos , Dor/metabolismo , Técnicas de Patch-Clamp , Ratos Sprague-Dawley , Medula Espinal/metabolismo
8.
Bioorg Med Chem ; 20(13): 4128-39, 2012 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-22626552

RESUMO

A novel 4-aminocyclopentapyrrolidine series of N-type Ca(2+) channel blockers have been discovered. Enantioselective synthesis of the 4-aminocyclopentapyrrolidines was enabled using N-tert-butyl sulfinamide chemistry. SAR studies demonstrate selectivity over L-type Ca(2+) channels. N-type Ca(2+) channel blockade was confirmed using electrophysiological recording techniques. Compound 25 is an N-type Ca(2+) channel blocker that produces antinociception in inflammatory and nociceptive pain models without exhibiting cardiovascular or motor liabilities.


Assuntos
Acetamidas/síntese química , Analgésicos/síntese química , Bloqueadores dos Canais de Cálcio/síntese química , Canais de Cálcio Tipo N/química , Pirrolidinas/química , Pirrolidinas/síntese química , Acetamidas/farmacologia , Acetamidas/uso terapêutico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo N/metabolismo , Modelos Animais de Doenças , Masculino , Dor/tratamento farmacológico , Pirrolidinas/farmacologia , Pirrolidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
9.
Assay Drug Dev Technol ; 10(6): 542-50, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22428804

RESUMO

Ca(V)2.2 (N-type) calcium channels are key regulators of neurotransmission. Evidence from knockout animals and localization studies suggest that Ca(V)2.2 channels play a critical role in nociceptive transmission. Additionally, ziconotide, a selective peptide inhibitor of Ca(V)2.2 channels, is clinically used to treat refractory pain. However, the use of ziconotide is limited by its low therapeutic index, which is believed, at least in part, to be a consequence of ziconotide inhibiting Ca(V)2.2 channels regardless of the channel state. Subsequent efforts have focused on the discovery of state-dependent inhibitors that preferentially bind to the inactivated state of Ca(V)2.2 channels in order to achieve an improved safety profile relative to ziconotide. Much less attention has been paid to understanding the binding kinetics of these state-dependent inhibitors. Here, we describe a novel electrophysiology-based assay on an automated patch platform designed to differentiate Ca(V)2.2 inhibitors based on their combined state dependence and kinetics. More specifically, this assay assesses inactivated state block, closed state block, and monitors the kinetics of recovery from block when channels move between states. Additionally, a use-dependent assay is described that uses a train of depolarizing pulses to drive channels to a similar level of inactivation for comparison. This use-dependent protocol also provides information on the kinetics of block development. Data are provided to show how these assays can be utilized to screen for kinetic diversity within and across chemical classes.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/efeitos dos fármacos , Eletrofisiologia/métodos , Animais , Automação , Bioensaio , Linhagem Celular , Interpretação Estatística de Dados , Avaliação Pré-Clínica de Medicamentos , Indóis/farmacologia , Cinética , Técnicas de Patch-Clamp , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Triazinas/farmacologia , Triazóis/farmacologia , ômega-Conotoxinas/farmacologia
10.
Bioorg Med Chem Lett ; 22(4): 1716-8, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22277280

RESUMO

A novel series of diphenyl lactam containing calcium channel blockers is described. Extensive SAR studies resulted in compounds with low molar activity and good plasma exposure after oral dosing. Compounds 2, 6 and 7 demonstrated significant efficacy in the capsaicin model of secondary hyperalgesia following oral administration.


Assuntos
Compostos de Bifenilo/síntese química , Bloqueadores dos Canais de Cálcio/síntese química , Canais de Cálcio Tipo N/metabolismo , Descoberta de Drogas , Lactamas/síntese química , Administração Oral , Animais , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacocinética , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacocinética , Concentração Inibidora 50 , Lactamas/química , Lactamas/farmacocinética , Estrutura Molecular , Piperazinas/química , Ratos , Solubilidade
11.
Biochem Pharmacol ; 83(3): 406-18, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22153861

RESUMO

Blockade of voltage-gated Ca²âº channels on sensory nerves attenuates neurotransmitter release and membrane hyperexcitability associated with chronic pain states. Identification of small molecule Ca²âº channel blockers that produce significant antinociception in the absence of deleterious hemodynamic effects has been challenging. In this report, two novel structurally related compounds, A-686085 and A-1048400, were identified that potently block N-type (IC50=0.8 µM and 1.4 µM, respectively) and T-type (IC50=4.6 µM and 1.2 µM, respectively) Ca²âº channels in FLIPR based Ca²âº flux assays. A-686085 also potently blocked L-type Ca²âº channels (EC50=0.6 µM), however, A-1048400 was much less active in blocking this channel (EC50=28 µM). Both compounds dose-dependently reversed tactile allodynia in a model of capsaicin-induced secondary hypersensitivity with similar potencies (EC50=300-365 ng/ml). However, A-686085 produced dose-related decreases in mean arterial pressure at antinociceptive plasma concentrations in the rat, while A-1048400 did not significantly alter hemodynamic function at supra-efficacious plasma concentrations. Electrophysiological studies demonstrated that A-1048400 blocks native N- and T-type Ca²âº currents in rat dorsal root ganglion neurons (IC50=3.0 µM and 1.6 µM, respectively) in a voltage-dependent fashion. In other experimental pain models, A-1048400 dose-dependently attenuated nociceptive, neuropathic and inflammatory pain at doses that did not alter psychomotor or hemodynamic function. The identification of A-1048400 provides further evidence that voltage-dependent inhibition of neuronal Ca²âº channels coupled with pharmacological selectivity vs. L-type Ca²âº channels can provide robust antinociception in the absence of deleterious effects on hemodynamic or psychomotor function.


Assuntos
Analgésicos/administração & dosagem , Bloqueadores dos Canais de Cálcio/administração & dosagem , Hemodinâmica/fisiologia , Neurônios/fisiologia , Medição da Dor , Piperidonas/administração & dosagem , Piperidonas/química , Administração Oral , Animais , Relação Dose-Resposta a Droga , Células HEK293 , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Neurônios/efeitos dos fármacos , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley
12.
Inflamm Res ; 60(7): 683-93, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21394563

RESUMO

OBJECTIVE: The aim of this study was to compare a diverse set of peptide and small-molecule calcium channel blockers for inactivated-state block of native and recombinant N-type calcium channels using fluorescence-based and automated patch-clamp electrophysiology assays. METHODS: The pharmacology of calcium channel blockers was determined at N-type channels in IMR-32 cells and in HEK cells overexpressing the inward rectifying K(+) channel Kir2.1. N-type channels were opened by increasing extracellular KCl. In the Kir2.1/N-type cell line the membrane potential could be modulated by adjusting the extracellular KCl, allowing determination of resting and inactivated-state block of N-type calcium channels. The potency and degree of state-dependent inhibition of these blockers were also determined by automated patch-clamp electrophysiology. RESULTS: N-type-mediated calcium influx in IMR-32 cells was determined for a panel of blockers with IC(50) values of 0.001-7 µM and this positively correlated with inactivated-state block of recombinant channels measured using electrophysiology. The potency of several compounds was markedly weaker in the state-dependent fluorescence-based assay compared to the electrophysiology assay, although the degree of state-dependent blockade was comparable. CONCLUSIONS: The present data demonstrate that fluorescence-based assays are suitable for assessing the ability of blockers to selectively interact with the inactivated state of the N-type channel.


Assuntos
Bloqueadores dos Canais de Cálcio/metabolismo , Canais de Cálcio Tipo N/metabolismo , Animais , Cálcio/metabolismo , Canais de Cálcio Tipo N/farmacologia , Linhagem Celular , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Técnicas de Patch-Clamp
13.
J Med Chem ; 51(22): 7094-8, 2008 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-18983139

RESUMO

cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4 (A-987306) is a new histamine H(4) antagonist. The compound is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. Compound 4 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 mumol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Benzofuranos/farmacologia , Hiperalgesia/tratamento farmacológico , Dor/prevenção & controle , Quinazolinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Benzofuranos/síntese química , Benzofuranos/química , Carragenina , Modelos Animais de Doenças , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Hiperalgesia/induzido quimicamente , Ligantes , Camundongos , Estrutura Molecular , Dor/fisiopatologia , Peritonite/tratamento farmacológico , Quinazolinas/síntese química , Quinazolinas/química , Ratos , Receptores Histamínicos , Receptores Histamínicos H4 , Estereoisomerismo , Relação Estrutura-Atividade
14.
Eur J Pharmacol ; 601(1-3): 8-15, 2008 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-18977214

RESUMO

We have recently identified three splice isoforms of the histamine H(3) receptor in multiple brain regions of cynomolgus monkey (Macaca fascicularis). Two of the novel isoforms displayed a deletion in the third intracellular loop (H(3)(413) and H(3)(410)), the third isoform H(3)(335) displayed a deletion in the i3 intracellular loop and a complete deletion of the putative fifth transmembrane domain TM5. We have confirmed by RT-PCR the expression of full-length H(3)(445) mRNA as well as H(3)(413), H(3)(410), and H(3)(335) splice isoform mRNA in multiple monkey brain regions including the frontal, parietal and occipital cortex, parahippocampal gyrus, hippocampus, amygdala, caudate nucleus, putamen, thalamus, hypothalamus, and cerebellum. The full-length isoform H(3)(445) was predominant in all of the regions tested, followed by H(3)(335), with the H(3)(413) and H(3)(410) being of low abundance. When expressed in C6 cells, H(3)(445), H(3)(413), and H(3)(410) exhibit high affinity binding to the agonist ligand [(3)H]-(N)-alpha-methylhistamine with respective pK(D) values of 9.7, 9.7, and 9.6. As expected, the H(3)(335) isoform did not display any saturable binding with [(3)H]-(N)-alpha-methylhistamine. The histamine H(3) receptor agonists histamine, (R)-alpha-methylhistamine, imetit and proxyfan were able to activate calcium mobilization responses through H(3)(445), H(3)(413) and H(3)(410) receptors when they were co-expressed with the chimeric G alpha(qi5)-protein in HEK293 cells, while no response was elicited in cells expressing the H(3)(335) isoform. The existence of multiple H(3) receptor splice isoforms across species raises the possibility that isoform specific properties including ligand affinity, signal transduction coupling, and brain localization may differentially contribute to observed in vivo effects of histamine H(3) receptor antagonists.


Assuntos
Expressão Gênica , RNA Mensageiro/metabolismo , Receptores Histamínicos H3/metabolismo , Animais , Encéfalo/metabolismo , Linhagem Celular , Clonagem Molecular , Agonistas dos Receptores Histamínicos/farmacologia , Humanos , Ligantes , Macaca fascicularis , Masculino , Ligação Proteica , Isoformas de Proteínas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Especificidade da Espécie
15.
J Med Chem ; 51(20): 6571-80, 2008 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-18811133

RESUMO

A series of 2-aminopyrimidines was synthesized as ligands of the histamine H4 receptor (H4R). Working in part from a pyrimidine hit that was identified in an HTS campaign, SAR studies were carried out to optimize the potency, which led to compound 3, 4- tert-butyl-6-(4-methylpiperazin-1-yl)pyrimidin-2-ylamine. We further studied this compound by systematically modifying the core pyrimidine moiety, the methylpiperazine at position 4, the NH2 at position 2, and positions 5 and 6 of the pyrimidine ring. The pyrimidine 6 position benefited the most from this optimization, especially in analogs in which the 6- tert-butyl was replaced with aromatic and secondary amine moieties. The highlight of the optimization campaign was compound 4, 4-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]benzonitrile, which was potent in vitro and was active as an anti-inflammatory agent in an animal model and had antinociceptive activity in a pain model, which supports the potential of H 4R antagonists in pain.


Assuntos
Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores Histamínicos/metabolismo , Animais , Biomarcadores , Antagonistas dos Receptores Histamínicos/química , Humanos , Hiperplasia/induzido quimicamente , Hiperplasia/prevenção & controle , Ligantes , Locomoção/efeitos dos fármacos , Camundongos , Estrutura Molecular , Pirimidinas/química , Ratos , Relação Estrutura-Atividade , Especificidade por Substrato
16.
Bioorg Med Chem Lett ; 18(1): 355-9, 2008 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-18077160

RESUMO

Structure-activity relationships (SAR) were analyzed within a library of diverse yet simple compounds prepared as histamine H3 antagonists. The libraries were constructed with a variety of low molecular weight pyrrolidines, selected from (R)-2-methylpyrrolidine, (S)-2-methylpyrrolidine, and pyrrolidine.


Assuntos
Antagonistas dos Receptores Histamínicos H3/química , Antagonistas dos Receptores Histamínicos H3/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Animais , Humanos , Cinética , Ratos , Relação Estrutura-Atividade
17.
J Biol Chem ; 282(5): 3146-56, 2007 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-17121830

RESUMO

Salvinorin A, the active component of the hallucinogenic sage Salvia divinorum, is an apparently selective and highly potent kappa-opioid receptor (KOR) agonist. Salvinorin A is unique among ligands for peptidergic G protein-coupled receptors in being nonnitrogenous and lipid-like in character. To examine the molecular basis for the subtype-selective binding of salvinorin A, we utilized an integrated approach using chimeric opioid receptors, site-directed mutagenesis, the substituted cysteine accessibility method, and molecular modeling and dynamics studies. We discovered that helix 2 is required for salvinorin A binding to KOR and that two residues (Val-108(2.53) and Val-118(2.63)) confer subtype selectivity. Intriguingly, molecular modeling studies predicted that these loci exhibit an indirect effect on salvinorin A binding, presumably through rotation of helix 2. Significantly, and in agreement with our in silico predictions, substituted cysteine accessibility method analysis of helix 2 comparing KOR and the delta-opioid receptor, which has negligible affinity for salvinorin A, revealed that residues known to be important for salvinorin A binding exhibit a differential pattern of water accessibility. These findings imply that differences in the helical orientation of helix 2 are critical for the selectivity of salvinorin A binding to KOR and provide a structurally novel basis for ligand selectivity.


Assuntos
Diterpenos/metabolismo , Receptores Acoplados a Proteínas G/química , Receptores Opioides kappa/química , Receptores Opioides kappa/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Linhagem Celular , Diterpenos Clerodânicos , Vetores Genéticos , Alucinógenos/metabolismo , Humanos , Rim , Cinética , Camundongos , Modelos Moleculares , Mutagênese Sítio-Dirigida , Conformação Proteica , Ensaio Radioligante , Receptores Opioides kappa/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo
18.
Mol Interv ; 6(5): 257-65, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17035666

RESUMO

The hallucinogenic plant Salvia divinorum (i.e., "magic mint") is a member of the Sage family that has been used for divination and shamanism by the Mazatecs. Over the past decade or so, S. divinorum has been increasingly used recreationally. The neoclerodane diterpene salvinorin A is the active component of S. divinorum, and recently, the kappa opioid receptor (KOR) has been identified, in vitro and in vivo, as its molecular target. The discovery of KOR as the molecular target of salvinorin A has opened up many opportunities for drug discovery and drug development for a number of psychiatric and non-psychiatric disorders.


Assuntos
Diterpenos , Doenças do Sistema Nervoso/tratamento farmacológico , Extratos Vegetais , Salvia/química , Animais , Diterpenos/química , Diterpenos/metabolismo , Diterpenos/uso terapêutico , Diterpenos Clerodânicos , Desenho de Fármacos , Alucinógenos/química , Alucinógenos/uso terapêutico , Humanos , Modelos Moleculares , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Extratos Vegetais/uso terapêutico , Ligação Proteica , Conformação Proteica , Receptores Opioides kappa/química , Receptores Opioides kappa/metabolismo , Transdução de Sinais/fisiologia , Relação Estrutura-Atividade
19.
Neuropharmacology ; 50(5): 576-84, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16376953

RESUMO

Acute activation of D2 dopamine receptors inhibits adenylyl cyclase (EC 4.6.1.1), whereas persistent activation of these inhibitory receptors results in a compensatory increase in cyclic AMP accumulation. This sensitization of adenylyl cyclase is thought to involve enhanced Galpha(s)-adenylyl cyclase interactions; however, the absolute requirement of Galpha(s) has not been determined. The present study used a Galpha(s)-deficient cell line to examine directly the role of Galpha(s) in D2 dopamine receptor-induced sensitization of recombinant adenylyl cyclase type 1 (AC1) and 5 (AC5). In acute experiments, quinpirole activation of the D2 dopamine receptor inhibited AC1 and AC5 activity, indicating that the acute regulatory properties of AC1 and AC5 were retained in the absence of Galpha(s). Subsequent experiments revealed that short-term (2 h) activation of the D2 dopamine receptor resulted in significantly enhanced forskolin-stimulated AC1 activity in the absence of Galpha(s), whereas sensitization of forskolin-stimulated AC5 activity appeared to require Galpha(s). The Galpha(s)-independent sensitization of AC1 was explored further using AC1-selective activation protocols (A23187 and CCE) following short- and long-term agonist treatment. These studies revealed that persistent activation of D2 dopamine receptors sensitized AC1 activity to Ca2+ stimulation in cells devoid of endogenous Galpha(s) and demonstrate directly that sensitization of AC1 is Galpha(s)-independent.


Assuntos
Adenilil Ciclases/metabolismo , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Receptores de Dopamina D2/fisiologia , Animais , Calcimicina/farmacologia , Cálcio/metabolismo , Colforsina/farmacologia , AMP Cíclico/metabolismo , AMP Cíclico/farmacocinética , Antagonistas dos Receptores de Dopamina D2 , Relação Dose-Resposta a Droga , Interações Medicamentosas , Ativação Enzimática/efeitos dos fármacos , Células Híbridas , Ionóforos/farmacologia , Isoproterenol/farmacologia , Camundongos , Quimpirol/farmacologia , RNA Mensageiro/biossíntese , Coelhos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Transfecção/métodos , Trítio/farmacocinética
20.
J Org Chem ; 70(24): 10057-61, 2005 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-16292839

RESUMO

[reaction: see text] Treatment of salvinorin A (1a) with KOH in MeOH gave the enedione 3, for which the dienone structure 7 was recently proposed. Also isolated, after methylation, were the secotriesters 4a-c. A mechanism for this unusual series of autoxidations is proposed. Surprisingly, 4a showed weak affinity at the kappa-opioid receptor. Divinatorins A-C (2a-c) showed no affinity at opioid receptors. Attempted reduction of 3 to a novel salvinorin diol (9d) was unsuccessful, but careful deacetylation of salvinorin C (9a) provided a viable route to this compound. A general method for identifying salvinorin 8-epimers by TLC is also presented.


Assuntos
Diterpenos/química , Diterpenos/síntese química , Diterpenos Clerodânicos , Hidróxidos/química , Metanol/química , Conformação Molecular , Oxirredução , Compostos de Potássio/química , Estereoisomerismo
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