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1.
Biochem Pharmacol ; 89(4): 536-44, 2014 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-24726441

RESUMO

Activation of T-type Ca²âº channels contributes to nociceptive signaling by facilitating action potential bursting and modulation of membrane potentials during periods of neuronal hyperexcitability. The role of T-type Ca²âº channels in chronic pain is supported by gene knockdown studies showing that decreased Ca(v)3.2 channel expression results in the loss of low voltage-activated (LVA) currents in dorsal root ganglion (DRG) neurons and attenuation of neuropathic pain in the chronic constriction injury (CCI) model. ABT-639 is a novel, peripherally acting, selective T-type Ca²âº channel blocker. ABT-639 blocks recombinant human T-type (Ca(v)3.2) Ca²âº channels in a voltage-dependent fashion (IC50 = 2 µM) and attenuates LVA currents in rat DRG neurons (IC50 = 8 µM). ABT-639 was significantly less active at other Ca²âº channels (e.g. Ca(v)1.2 and Ca(v)2.2) (IC50 > 30 µM). ABT-639 has high oral bioavailability (%F = 73), low protein binding (88.9%) and a low brain:plasma ratio (0.05:1) in rodents. Following oral administration ABT-639 produced dose-dependent antinociception in a rat model of knee joint pain (ED50 = 2 mg/kg, p.o.). ABT-639 (10-100 mg/kg, p.o.) also increased tactile allodynia thresholds in multiple models of neuropathic pain (e.g. spinal nerve ligation, CCI, and vincristine-induced). [corrected]. ABT-639 did not attenuate hyperalgesia in inflammatory pain models induced by complete Freund's adjuvant or carrageenan. At higher doses (e.g. 100-300 mg/kg) ABT-639 did not significantly alter hemodynamic or psychomotor function. The antinociceptive profile of ABT-639 provides novel insights into the role of peripheral T-type (Ca(v)3.2) channels in chronic pain states.


Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo T/metabolismo , Modelos Animais de Doenças , Compostos Heterocíclicos com 2 Anéis/uso terapêutico , Proteínas do Tecido Nervoso/antagonistas & inibidores , Neuralgia/tratamento farmacológico , Dor Nociceptiva/tratamento farmacológico , Nervos Periféricos/efeitos dos fármacos , Sulfonamidas/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Disponibilidade Biológica , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/farmacocinética , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/química , Canais de Cálcio Tipo T/genética , Células Cultivadas , Dor Crônica/tratamento farmacológico , Dor Crônica/metabolismo , Relação Dose-Resposta a Droga , Compostos Heterocíclicos com 2 Anéis/efeitos adversos , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Compostos Heterocíclicos com 2 Anéis/farmacologia , Humanos , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neuralgia/metabolismo , Dor Nociceptiva/metabolismo , Nervos Periféricos/citologia , Nervos Periféricos/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia
2.
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
4.
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
5.
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
6.
Arch Toxicol ; 85(5): 513-23, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21046364

RESUMO

Dibromoacetic acid (DBAA), a by-product formed during disinfection of drinking water, alters spermatogenesis in rats through defective spermiation. The mechanism underlying this toxicity is not fully understood. In this study, gene expression data generated with microarrays from testes were used to generate a mechanistic understanding of DBAA-induced testicular toxicity. Testes were collected from male Sprague-Dawley rats dosed orally for 1 and 4 days with DBAA at 250 mg/kg/day. At both time points, DBAA administration induced delayed spermiation in Stage X tubules and regulated the expression of a small number of genes, including a mild but consistent downregulation of cytochrome P450c17α (CYP17) mRNA, an enzyme expressed by Leydig cells and essential for the production of testicular androgens. Downregulation of CYP17 was confirmed at the protein level and its biological significance was substantiated by demonstrating reduced testicular testosterone levels in DBAA-dosed rats. Furthermore, testosterone production by human chorionic gonadotrophin (hCG)-stimulated rat primary Leydig cells was reduced following treatment with 100 µM DBAA. Collectively, these results indicate that DBAA can directly target rat Leydig cells and downregulate testicular CYP17 expression with a resulting decreased testicular testosterone production. This disruption of testicular steroidogenesis is likely to contribute to the mechanism of failed spermiation observed in rats following exposure to DBAA.


Assuntos
Acetatos/toxicidade , Esteroide 17-alfa-Hidroxilase/metabolismo , Doenças Testiculares/patologia , Testículo/patologia , Animais , Gonadotropina Coriônica/metabolismo , Regulação para Baixo , Perfilação da Expressão Gênica , Humanos , Células Intersticiais do Testículo/metabolismo , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Espermatogênese/efeitos dos fármacos , Esteroide 17-alfa-Hidroxilase/genética , Doenças Testiculares/induzido quimicamente , Testosterona/biossíntese
7.
Bioorg Med Chem Lett ; 20(6): 1900-4, 2010 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-20171098

RESUMO

Three novel series of histamine H(4) receptor (H(4)R) antagonists containing the 2-aminopyrimidine motif are reported. The best of these compounds display good in vitro potency in both functional and binding assays. In addition, representative compounds are able to completely block itch responses when dosed ip in a mouse model of H(4)-agonist induced scratching, thus demonstrating their activities as H(4)R antagonists.


Assuntos
Aminopiridinas/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Animais , Humanos , Camundongos , Receptores Histamínicos , Receptores Histamínicos H4
8.
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
9.
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
10.
J Med Chem ; 51(20): 6547-57, 2008 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-18817367

RESUMO

A new structural class of histamine H 4 receptor antagonists (6-14) was designed based on rotationally restricted 2,4-diaminopyrimidines. Series compounds showed potent and selective in vitro H 4 antagonism across multiple species, good CNS penetration, improved PK properties compared to reference H 4 antagonists, functional H 4 antagonism in cellular and in vivo pharmacological assays, and in vivo anti-inflammatory and antinociceptive efficacy. One compound, 10 (A-943931), combined the best features of the series in a single molecule and is an excellent tool compound to probe H 4 pharmacology. It is a potent H 4 antagonist in functional assays across species (FLIPR Ca (2+) flux, K b < 5.7 nM), has high (>190x) selectivity for H 4, and combines good PK in rats and mice (t 1/2 of 2.6 and 1.6 h, oral bioavailability of 37% and 90%) with anti-inflammatory activity (ED 50 = 37 micromol/kg, mouse) and efficacy in pain models (thermal hyperalgesia, ED 50 = 72 micromol/kg, rat).


Assuntos
Aminas/química , Anti-Inflamatórios/síntese química , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/uso terapêutico , Dor/tratamento farmacológico , Pirimidinas/síntese química , Receptores Histamínicos/metabolismo , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/classificação , Anti-Inflamatórios/uso terapêutico , Modelos Animais de Doenças , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/classificação , Ligantes , Camundongos , Estrutura Molecular , Pirimidinas/química , Pirimidinas/classificação , Pirimidinas/uso terapêutico , Ratos
11.
Biochem Pharmacol ; 73(8): 1243-55, 2007 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-17371699

RESUMO

Three novel heterocyclic benzofurans A-688057 (1), A-687136 (2), and A-698418 (3) were profiled for their in vitro and in vivo properties as a new series of histamine H(3) receptor antagonists. The compounds were all found to have nanomolar potency in vitro at histamine H(3) receptors, and when profiled in vivo for CNS activity, all were found active in an animal behavioral model of attention. The compound with the most benign profile versus CNS side effects was selected for greater scrutiny of its in vitro properties and overall drug-likeness. This compound, A-688057, in addition to its potent and robust efficacy in two rodent behavioral models at blood levels ranging 0.2-19 nM, possessed other favorable features, including high selectivity for H(3) receptors (H(3), K(i)=1.5 nM) versus off-target receptors and channels (including the hERG K(+) channel, K(i)>9000 nM), low molecular weight (295), high solubility, moderate lipophilicity (logD(pH7.4)=2.05), and good CNS penetration (blood/brain 3.4x). In vitro toxicological tests indicated low potential for phospholipidosis, genotoxicity, and CYP(450) inhibition. Even though pharmacokinetic testing uncovered only moderate to poor oral bioavailability in rat (26%), dog (30%), and monkey (8%), and only moderate blood half-lives after i.v. administration (t(1/2) in rat of 2.9h, 1.7h in dog, 1.8h in monkey), suggesting poor human pharmacokinetics, the data overall indicated that A-688057 has an excellent profile for use as a pharmacological tool compound.


Assuntos
Comportamento Animal/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/farmacologia , Receptores Histamínicos H3/fisiologia , Animais , Comportamento Animal/fisiologia , Benzofuranos/química , Benzofuranos/farmacologia , Cães , Haplorrinos , Antagonistas dos Receptores Histamínicos/sangue , Humanos , Ratos , Receptores Histamínicos H3/efeitos dos fármacos
12.
J Med Chem ; 49(23): 6869-87, 2006 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-17154517

RESUMO

Structure-activity relationships were investigated on the tricyclic dihydropyridine (DHP) KATP openers 9-(3-bromo-4-fluorophenyl)-5,9-dihydro-3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (6) and 10-(3-bromo-4-fluorophenyl)-9,10-dihydro-1H,8H-2,7-dioxa-9-azaanthracene-4,5-dione (65). Substitution off the core of the DHP, absolute stereochemistry, and aromatic substitution were evaluated for KATP channel activity using Ltk- cells stably transfected with the Kir6.2/SUR2B exon 17- splice variant and in an electrically stimulated pig bladder strip assay. A select group of compounds was evaluated for in vitro inhibition of spontaneous bladder contractions. Several compounds were found to have the unique characteristic of partial efficacy in both the cell-based and electrically stimulated bladder strip assays but full efficacy in inhibiting spontaneous bladder strip contractions. For compound 23b, this profile was mirrored in vivo where it was fully efficacious in inhibiting spontaneous myogenic bladder contractions but only partially able to reduce neurogenically mediated reflex bladder contractions.


Assuntos
Trifosfato de Adenosina/fisiologia , Compostos Aza/síntese química , Di-Hidropiridinas/química , Compostos Heterocíclicos com 3 Anéis/síntese química , Naftalenos/síntese química , Canais de Potássio Corretores do Fluxo de Internalização/efeitos dos fármacos , Animais , Compostos Aza/química , Compostos Aza/farmacologia , Linhagem Celular , Cristalografia por Raios X , Estimulação Elétrica , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Técnicas In Vitro , Ativação do Canal Iônico , Camundongos , Contração Muscular , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Naftalenos/química , Naftalenos/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Suínos , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiologia
13.
Eur J Pharmacol ; 532(1-2): 107-14, 2006 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-16487510

RESUMO

Partial bladder outlet obstruction of the pig is considered as a valuable preclinical model for evaluating the profile of compounds for the treatment of bladder overactivity. In this study, we characterized the pharmacological properties of isolated bladder smooth muscle from pigs following partial outlet obstruction and its sensitivity to potassium channel openers. Bladder strips from obstructed animals showed significantly lower maximal efficacy (E(max)) and sensitivity to stimulation by ATP and carbachol, but not to those evoked by serotonin, compared to age-matched controls. Tissue strips from obstructed animals also showed a 2.5-fold increase in the potency and significantly reduced maximum response following K+ depolarization. With respect to spontaneous activity, bladder strips from control strips demonstrated little spontaneous phasic activity at all preloads examined. In contrast, bladder strips from obstructed animals showed large preload-dependent increases in spontaneous phasic activity at preload values of 16-32 g. The potencies of K(ATP) channel openers to relax carbachol-evoked contractions showed a good 1:1 correlation (r(2)=0.90) between obstructed and control bladder strips. These studies demonstrate that obstructed pig bladders show enhanced spontaneous phasic activity especially at elevated preloads, which may underlie unstable myogenic bladder contractions reported in cystometrographic measurements in vivo. The impaired responses to electrical field stimulation could be attributed to reduced efficacies and/or lower sensitivities of muscarinic and purinergic signaling pathways. K(ATP) channel sensitivities remain essentially unimpaired in the obstructed bladder and could be effectively modulated by openers with potential for the treatment of overactive bladder secondary to outlet obstruction.


Assuntos
Contração Muscular/fisiologia , Músculo Liso/fisiopatologia , Obstrução do Colo da Bexiga Urinária/fisiopatologia , Trifosfato de Adenosina/farmacologia , Amidas/farmacologia , Animais , Benzofenonas/farmacologia , Carbacol/farmacologia , Agonistas Colinérgicos/farmacologia , Cromakalim/farmacologia , Óxidos S-Cíclicos/farmacologia , Diazóxido/farmacologia , Relação Dose-Resposta a Droga , Estimulação Elétrica , Feminino , Guanidinas/farmacologia , Histamina/farmacologia , Hipertrofia , Técnicas In Vitro , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Canais de Potássio/agonistas , Canais de Potássio/fisiologia , Cloreto de Potássio/farmacologia , Piridinas/farmacologia , Quinolonas/farmacologia , Serotonina/farmacologia , Serotoninérgicos/farmacologia , Suínos , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologia , Bexiga Urinária/fisiopatologia , Vasodilatadores/farmacologia
14.
J Pharmacol Exp Ther ; 314(1): 271-81, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15821027

RESUMO

Previously reported pharmacological studies using the imidazole-containing histamine H3 receptor ligands GT-2331 (Cipralisant) and proxyfan resulted in a range of classifications (antagonist, agonist, and protean) for these compounds. We examined the role that the signaling system, with particular emphasis on the type of G protein, had on the pharmacology observed for H3 ligands. Ligands were assessed using assays measuring neurotransmitter release, cAMP, and guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding. Whereas clobenpropit and ciproxifan were consistently antagonists, GT-2331, proxyfan, and imetit exhibited differential activity. Although GT-2331 and proxyfan exhibited little agonist activity in neurotransmitter release assays, both demonstrated full agonism relative to (R)-alpha-methylhistamine in cAMP assays. In [35S]GTPgammaS binding assays, GT-2331 and proxyfan demonstrated partial agonism. Imetit showed full agonism in most assays, but it was slightly less efficacious in a neurotransmitter release assay and in [35S]GTPgammaS binding at the human H3 receptor. To further examine these ligands, we coexpressed G alpha16 or chimeric G alpha q/i5 in human embryonic kidney cells expressing the human H3 receptor and assayed intracellular calcium and cAMP levels. GT-2331, proxyfan, and imetit demonstrated full agonism in all assays of cAMP activity. However, in cells expressing G alpha16, they exhibited minimal agonism in calcium mobilization assays, whereas imetit showed partial agonism. When G alpha q/i5 was used, the activity of both GT-2331 and proxyfan increased, whereas imetit became a full agonist. These results demonstrate that GT-2331 and proxyfan's differential pharmacology at the H3 receptor depends on the type of G protein used and provide indirect evidence for differential ligand-bound active states that mediate signaling by the H3 receptor.


Assuntos
Proteínas de Ligação ao GTP/fisiologia , Receptores Histamínicos H3/efeitos dos fármacos , Animais , AMP Cíclico/metabolismo , Estimulação Elétrica , Proteínas de Ligação ao GTP/química , Proteínas de Ligação ao GTP/genética , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Cobaias , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Liberação de Histamina/efeitos dos fármacos , Íleo/efeitos dos fármacos , Íleo/metabolismo , Imidazóis/farmacologia , Ligantes , Masculino , Membranas/metabolismo , Neurotransmissores/metabolismo , Conformação Proteica , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transfecção
15.
Br J Pharmacol ; 143(1): 81-90, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15302680

RESUMO

1. Openers of ATP-sensitive K(+) channels are of interest in several therapeutic indications including overactive bladder and other lower urinary tract disorders. This study reports on the in vitro and in vivo characterization of a structurally novel naphthylamide N-[2-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-naphthalen-1-yl]-acetamide (A-151892), as an opener of the ATP-sensitive potassium channels. 2. A-151892 was found to be a potent and efficacious potassium channel opener (KCO) as assessed by glibenclamide-sensitive whole-cell current and fluorescence-based membrane potential responses (-log EC(50)=7.63) in guinea-pig bladder smooth muscle cells. 3. Evidence for direct interaction with KCO binding sites was derived from displacement of binding of the 1,4-dihydropyridine opener [(125)I]A-312110. A-151892 displaced [(125)I]A-312110 binding to bladder membranes with a -log Ki value of 7.45, but lacked affinity against over 70 neurotransmitter receptor and ion channel binding sites. 4. In pig bladder strips, A-151892 suppressed phasic, carbachol-evoked and electrical field stimulus-evoked contractility in a glibenclamide-reversible manner with -log IC(50) values of 8.07, 7.33 and 7.02 respectively, comparable to that of the potencies of the prototypical cyanoguanidine KCO, P1075. The potencies to suppress contractions in thoracic aorta (-log IC(50)=7.81) and portal vein (-log IC(50)=7.98) were not substantially different from those observed for suppression of phasic contractility of the bladder smooth muscle. 5. In vivo, A-151892 was found to potently suppress unstable bladder contractions in obstructed models of unstable contractions in both pigs and rats with pED(35%) values of 8.05 and 7.43, respectively. 6. These results demonstrate that naphthylamide analogs exemplified by A-151892 are novel K(ATP) channel openers and may serve as chemotypes to exploit additional analogs with potential for the treatment of overactive bladder and lower urinary tract symptoms.


Assuntos
Acetamidas/farmacologia , Trifosfato de Adenosina/fisiologia , Naftalenos/farmacologia , Canais de Potássio/agonistas , Animais , Barbitúricos/metabolismo , Ligação Competitiva/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Vasos Sanguíneos/efeitos dos fármacos , Feminino , Guanidinas/farmacologia , Cobaias , Técnicas In Vitro , Radioisótopos do Iodo , Isoxazóis/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Técnicas de Patch-Clamp , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Suínos , Bexiga Urinária/efeitos dos fármacos
16.
J Med Chem ; 47(12): 3163-79, 2004 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-15163196

RESUMO

Structure-activity relationships were investigated on a novel series of sulfonyldihydropyridine-containing K(ATP) openers. Ring sizes, absolute stereochemistry, and aromatic substitution were evaluated for K(ATP) activity in guinea pig bladder cells using a fluorescence-based membrane potential assay and in a pig bladder strip assay. The inhibition of spontaneous bladder contractions in vitro was also examined for a select group of compounds. All compounds studied showed greater potency to inhibit spontaneous bladder contractions relative to their potencies to inhibit contractions elicited by electrical stimulation. In an anesthetized pig model of myogenic bladder overactivity, compound 14 and (-)-cromakalim 1 were found to inhibit spontaneous bladder contractions in vivo at plasma concentrations lower than those that affected hemodynamic parameters. Compound 14 showed approximately 5-fold greater selectivity than 1 in vivo and supports the concept that bladder-selective K(ATP) channel openers may have utility in the treatment of overactive bladder.


Assuntos
Trifosfato de Adenosina/fisiologia , Óxidos S-Cíclicos/síntese química , Canais de Potássio/efeitos dos fármacos , Quinolonas/síntese química , Bexiga Urinária/efeitos dos fármacos , Animais , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacologia , Estimulação Elétrica , Cobaias , Hemodinâmica/efeitos dos fármacos , Técnicas In Vitro , Potenciais da Membrana , Contração Muscular/efeitos dos fármacos , Músculo Liso/citologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Quinolonas/química , Quinolonas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Suínos , Bexiga Urinária/citologia , Bexiga Urinária/fisiologia , Urodinâmica/efeitos dos fármacos
17.
J Med Chem ; 47(12): 3180-92, 2004 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-15163197

RESUMO

Structure-activity relationships were investigated on a novel series of tricyclic dihydropyridine-containing K(ATP) openers. This diverse group of analogues, comprising a variety of heterocyclic rings fused to the dihydropyridine nucleus, was designed to determine the influence on activity of hydrogen-bond-donating and -accepting groups and their stereochemical disposition. Compounds were evaluated for K(ATP) activity in guinea pig bladder cells using a fluorescence-based membrane potential assay and in a pig bladder strip assay. The inhibition of spontaneous bladder contractions in vitro was also examined for a subset of compounds. All compounds studied showed greater potency to inhibit spontaneous bladder contractions relative to their potencies to inhibit contractions elicited by electrical stimulation.


Assuntos
Trifosfato de Adenosina/fisiologia , Di-Hidropiridinas/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Canais de Potássio/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Animais , Di-Hidropiridinas/química , Di-Hidropiridinas/farmacologia , Estimulação Elétrica , Cobaias , Hemodinâmica/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Ligação de Hidrogênio , Técnicas In Vitro , Potenciais da Membrana , Contração Muscular/efeitos dos fármacos , Músculo Liso/citologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Estereoisomerismo , Relação Estrutura-Atividade , Suínos , Bexiga Urinária/citologia , Bexiga Urinária/fisiologia , Urodinâmica/efeitos dos fármacos
18.
J Med Chem ; 47(12): 3220-35, 2004 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-15163201

RESUMO

Structure-activity studies were performed on the alpha(1A)-adrenoceptor (AR) selective agonist N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide (4). Compounds were evaluated for binding activity at the alpha(1A), alpha(1b), alpha(1d), alpha(2a), and alpha(2B) subtypes. Functional activity in tissues containing the alpha(1A) (rabbit urethra), alpha(1B) (rat spleen), alpha(1D) (rat aorta), and alpha(2A) (rat prostatic vas deferens) was also evaluated. A dog in vivo model simultaneously measuring intraurethral pressure (IUP) and mean arterial pressure (MAP) was used to assess the uroselectivity of the compounds. Many of the compounds that were highly selective in vitro for the alpha(1A)-AR subtype were also more uroselective in vivo for increasing IUP over MAP than the nonselective alpha(1)-agonists phenylpropanolamine (PPA) (1) and ST-1059 (2, the active metabolite of midodrine), supporting the hypothesis that greater alpha(1A) selectivity would reduce cardiovascular side effects. However, the data also support a prominent role of the alpha(1A)-AR subtype in the control of MAP.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 1 , Imidazóis/síntese química , Naftalenos/síntese química , Sulfonamidas/síntese química , Tetra-Hidronaftalenos/síntese química , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Cães , Feminino , Imidazóis/química , Imidazóis/farmacologia , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Naftalenos/química , Naftalenos/farmacologia , Coelhos , Ensaio Radioligante , Ratos , Receptores Adrenérgicos alfa 1 , Baço/efeitos dos fármacos , Baço/fisiologia , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacologia , Uretra/efeitos dos fármacos , Uretra/fisiologia , Ducto Deferente/efeitos dos fármacos , Ducto Deferente/fisiologia
19.
Naunyn Schmiedebergs Arch Pharmacol ; 369(5): 481-9, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15095032

RESUMO

Calcium activated K(+) channels (K(Ca) channels) are found in a variety of smooth muscle tissues, the most characterized of which are the large conductance K(Ca) channels (BK(Ca) or maxi-K(+) channels). Recent medicinal chemistry efforts have identified novel BK(Ca) openers including 2-amino-5-(2-fluoro-phenyl)-4-methyl-1H-pyrrole-3-carbonitrile (NS-8), BMS-204352 and its analog 3-(5-chloro-2-hydroxy-phenyl)-3-hydroxy-6-trifluoromethyl-1,3-dihydro-indol-2-one (compound 1), and 5,7-dichloro-4-(5-chloro-2-hydroxy-phenyl)-3-hydroxy-1H-quinolin-2-one (compound 2). Although these compounds are effective BK(Ca) openers as shown by electrophysiological methods, little is known about their effects on smooth muscle contractility. In this study, the responsiveness of structurally diverse BK(Ca) openers-NS-8, compounds 1 and 2 and the well characterized nonselective NS-1619-was assessed using segments of endothelium denuded rat aorta, rat and guinea pig detrusor precontracted with extracellular K(+), and Landrace pig detrusor stimulated by electrical field. In all preparations, the compounds tested inhibited or completely abolished contractions with similar potencies (-logIC(50) values: 3.8 to 5.1). In rat aorta, in the presence of 80 mM K(+), the compounds significantly shifted the concentration-response curve to the right compared with those obtained in 30 mM K(+). These data are consistent with K(+) channel (BK(Ca) channel) activation as the underlying mechanism of relaxation by compounds that share the electrophysiological property of BK(Ca) current activation. The similar potencies at detrusor and vascular smooth muscle suggest that the achievement of smooth muscle selectivity in vitro with the representative compounds examined in this study may prove to be a challenge when targeting BK(Ca) channels for smooth muscle indications such as overactive bladder.


Assuntos
Benzimidazóis/farmacologia , Indóis/farmacologia , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Canais de Potássio Cálcio-Ativados/efeitos dos fármacos , Pirróis/farmacologia , Bexiga Urinária/efeitos dos fármacos , Animais , Estimulação Elétrica , Cobaias , Ratos
20.
Mol Pharmacol ; 64(1): 143-53, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12815170

RESUMO

Although ATP-sensitive K+ channels continue to be explored for their therapeutic potential, developments in high-affinity radioligands to investigate native and recombinant KATP channels have been less forthcoming. This study reports the identification and pharmacological characterization of a novel iodinated 1,4-dihydropyridine KATP channel opener, [125I]A-312110 [(9R)-9-(4-fluoro-3-125iodophenyl)-2,3,5,9-tetrahydro-4H-pyrano[3,4-b]thieno[2,3-e]pyridin-8(7H)-one-1,1-dioxide]. Binding of [125I]A-312110 to guinea pig cardiac (KD = 5.8 nM) and urinary bladder (KD = 4.9 nM) membranes were of high affinity, saturable, and to a single set of binding sites. Displacement of [125I]A-312110 by structurally diverse potassium channel openers (KCOs) indicated a similar rank order of potency in both guinea pig cardiac and bladder membranes (Ki, heart): A-312110 (4.3 nM) > N-cyano-N'-(1,1-dimethylpropyl)-N"-3-pyridylguanidine (P1075) > (-)-N-(2-ethoxyphenyl)-N'-(1,2,3-trimethylpropyl)-2-nitroethene-1,1-diamine (Bay X 9228) > pinacidil > (-)-cromakalim > N-(4-benzoyl phenyl)-3,3,3-trifluro-2-hydroxy-2-methylpropionamine (ZD6169) > 9-(3-cyanophenyl)-3,4,6,7,9,10-hexahydro-1,8-(2H,5H)-acridinedione (ZM244085) >> diazoxide (16.7 microM). Displacement by KATP channel blockers, the sulfonylurea glyburide, and the cyanoguanidine N-[1-(3-chlorophenyl)cyclobutyl]-N'-cyano-N"-3-pyridinyl-guanidine (PNU-99963) were biphasic in the heart but monophasic in bladder with about a 100- to 500-fold difference in Ki values between high- and low-affinity sites. Good correlations were observed between cardiac or bladder-binding affinities of KCOs with functional activation as assessed by their respective potencies to either suppress action potential duration (APD) in Purkinje fibers or to relax electrical field-stimulated bladder contractions. Collectively, these results demonstrate that [125I]A-312110 binds with high affinity and has an improved activity profile compared with other radiolabeled KCOs. [125I]A-312110 is a useful tool for investigation of the molecular and functional properties of the KATP channel complex and for the identification, in a high throughput manner, of both novel channel blockers and openers that interact with cardiac/smooth muscle-type KATP channels.


Assuntos
Coração/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Piridinas/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Tiofenos/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Sítios de Ligação , Di-Hidropiridinas/química , Cobaias , Radioisótopos do Iodo , Cinética , Masculino , Proteínas de Membrana/efeitos dos fármacos , Miocárdio/metabolismo , Canais de Potássio , Ensaio Radioligante , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo
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