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1.
J Pharmacol Exp Ther ; 343(1): 233-45, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22815533

RESUMO

Blockade of the histamine H(3) receptor (H(3)R) enhances central neurotransmitter release, making it an attractive target for the treatment of cognitive disorders. Here, we present in vitro and in vivo pharmacological profiles for the H(3)R antagonist 2-[4'-((3aR,6aR)-5-methyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-biphenyl-4-yl]-2H-pyridazin-3-one (ABT-288). ABT-288 is a competitive antagonist with high affinity and selectivity for human and rat H(3)Rs (K(i) = 1.9 and 8.2 nM, respectively) that enhances the release of acetylcholine and dopamine in rat prefrontal cortex. In rat behavioral tests, ABT-288 improved acquisition of a five-trial inhibitory avoidance test in rat pups (0.001-0.03 mg/kg), social recognition memory in adult rats (0.03-0.1 mg/kg), and spatial learning and reference memory in a rat water maze test (0.1-1.0 mg/kg). ABT-288 attenuated methamphetamine-induced hyperactivity in mice. In vivo rat brain H(3)R occupancy of ABT-288 was assessed in relation to rodent doses and exposure levels in behavioral tests. ABT-288 demonstrated a number of other favorable attributes, including good pharmacokinetics and oral bioavailability of 37 to 66%, with a wide central nervous system and cardiovascular safety margin. Thus, ABT-288 is a selective H(3)R antagonist with broad procognitive efficacy in rodents and excellent drug-like properties that support its advancement to the clinical area.


Assuntos
Cognição/efeitos dos fármacos , Cognição/fisiologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Nootrópicos/farmacologia , Piridazinas/farmacologia , Pirróis/farmacologia , Receptores Histamínicos H3/fisiologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Cobaias , Células HEK293 , Antagonistas dos Receptores Histamínicos H3/química , Humanos , Masculino , Camundongos , Nootrópicos/química , Ligação Proteica/fisiologia , Piridazinas/química , Pirróis/química , Ratos , Ratos Endogâmicos SHR , Ratos Long-Evans , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia
2.
J Med Chem ; 50(24): 6265-73, 2007 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-17973362

RESUMO

A series of novel cyanoguanidine derivatives was designed and synthesized. Condensation of N-(1-benzotriazol-1-yl-2,2-dichloropropyl)-substituted benzamides with N-(substituted-pyridin-3-yl)-N'-cyanoguanidines furnished N-{2,2-dichloro-1-[N'-(substituted-pyridin-3-yl)-N''-cyanoguanidino]propyl}-substituted benzamide derivatives. These agents were glyburide-reversible potassium channel openers and hyperpolarized human bladder cells as assessed by the FLIPR membrane potential dye (KATP-FMP). These compounds were also potent full agonists in relaxing electrically stimulated pig bladder strips, an in vitro model of overactive bladder. The most active compound 9 was evaluated for in vivo efficacy and selectivity in a pig model of bladder instability. Preliminary pharmacokinetic studies in dog demonstrated excellent oral bioavailability and a t1/2 of 15 h. The synthesis, SAR studies, and biological properties of these agents are discussed.


Assuntos
Benzamidas/síntese química , Guanidinas/síntese química , Canais KATP/fisiologia , Bexiga Urinária Hiperativa/tratamento farmacológico , Administração Oral , Animais , Benzamidas/farmacocinética , Benzamidas/farmacologia , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Estimulação Elétrica , Feminino , Guanidinas/farmacocinética , Guanidinas/farmacologia , Humanos , Técnicas In Vitro , Ativação do Canal Iônico , Canais KATP/agonistas , Relaxamento Muscular , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Canais de Potássio Corretores do Fluxo de Internalização/agonistas , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Relação Estrutura-Atividade , Suínos , Bexiga Urinária/citologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiologia , Bexiga Urinária Hiperativa/fisiopatologia , Urodinâmica
3.
J Med Chem ; 50(1): 149-64, 2007 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-17201418

RESUMO

Starting from a rapidly metabolized adamantane 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor 22a, a series of E-5-hydroxy-2-adamantamine inhibitors, exemplified by 22d and (+/-)-22f, was discovered. Many of these compounds are potent inhibitors of 11beta-HSD1 and are selective over 11beta-HSD2 for multiple species (human, mouse, and rat), unlike other reported species-selective series. These compounds have good cellular potency and improved microsomal stability. Pharmacokinetic profiling in rodents indicated moderate to large volumes of distribution, short half-lives, and a pharmacokinetic species difference with the greatest exposure measured in rat with 22d. One hour postdose liver, adipose, and brain tissue 11beta-HSD1 inhibition was confirmed with (+/-)-22f in a murine ex vivo assay. Although 5,7-disubstitued-2-adamantamines provided greater stability, a single, E-5-position, polar functional group afforded inhibitors with the best combination of stability, potency, and selectivity. These results indicate that adamantane metabolic stabilization sufficient to obtain short-acting, potent, and selective 11beta-HSD1 inhibitors has been discovered.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/análogos & derivados , Adamantano/síntese química , Piperazinas/síntese química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , Adamantano/farmacocinética , Animais , Linhagem Celular , Humanos , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/metabolismo , Piperazinas/farmacocinética , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição Tecidual
4.
J Med Chem ; 49(15): 4459-69, 2006 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-16854051

RESUMO

The discovery and pharmacological evaluation of potent, selective, and orally bioavailable growth hormone secretagogue receptor (GHS-R) antagonists are reported. Previously, 2,4-diaminopyrimidine-based GHS-R antagonists reported from our laboratories have been shown to be dihydrofolate reductase (DHFR) inhibitors. By comparing the X-ray crystal structure of DHFR docked with our GHS-R antagonists and GHS-R modeling, we designed and synthesized a series of potent and DHFR selective GHS-R antagonists with good pharmacokinetic (PK) profiles. An amide derivative 13d (Ca2+ flux IC50 = 188 nM, [brain]/[plasma] = 0.97 @ 8 h in rat) showed a 10% decrease in 24 h food intake in rats, and over 5% body weight reduction after 14-day oral treatment in diet-induced obese (DIO) mice. In comparison, a urea derivative 14c (Ca2+ flux IC50 = 7 nM, [brain]/[plasma] = 0.0 in DIO) failed to show significant effect on food intake in the acute feeding DIO model. These observations demonstrated for the first time that peripheral GHS-R blockage with small molecule GHS-R antagonists might not be sufficient for suppressing appetite and inducing body weight reduction.


Assuntos
Aminopiridinas/síntese química , Fármacos Antiobesidade/síntese química , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Administração Oral , Amidas/síntese química , Amidas/farmacologia , Aminopiridinas/farmacologia , Animais , Fármacos Antiobesidade/farmacologia , Depressores do Apetite/síntese química , Depressores do Apetite/farmacologia , Disponibilidade Biológica , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Cristalografia por Raios X , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Modelos Moleculares , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Receptores de Grelina , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacologia
5.
J Med Chem ; 49(8): 2568-78, 2006 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-16610800

RESUMO

Ghrelin, a gut-derived orexigenic hormone, is an endogenous ligand of the growth hormone secretagogue receptor (GHS-R). Centrally administered ghrelin has been shown to cause hunger and increase food intake in rodents. Inhibition of ghrelin actions with ghrelin antibody, peptidyl GHS-R antagonists, and antisense oligonucleosides resulted in weight loss and food intake decrease in rodents. Here we report the effects of GHS-R antagonists, some of which were potent, selective, and orally bioavailable. A structure-activity relationship study led to the discovery of 8a, which was effective in decreasing food intake and body weight in several acute rat studies.


Assuntos
Pirimidinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligantes , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Receptores de Grelina , Estereoisomerismo , Relação Estrutura-Atividade , Fatores de Tempo
6.
Curr Opin Investig Drugs ; 7(3): 206-13, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16555680

RESUMO

Vitamin D3 is modified by vitamin D3 25-hydroxylase in the liver, and by 25-hydroxyvitamin D3 1alpha-hydroxylase (CYP27B1) in the kidney, to form the active metabolite 1alpha,25-dihydroxyvitamin D3. Several vitamin D receptor (VDR) activators, including paricalcitol and calcitriol, are currently available for the treatment of hyperparathyroidism secondary to chronic kidney disease (CKD). CKD patients encounter a much higher risk of cardiovascular disease than do members of the general public, and recent clinical observations have shown that VDR activator therapy provides survival benefit for CKD patients in the rank order of paricalcitol > calcitriol > no VDR activator therapy, independent of parathyroid hormone, phosphorus and calcium. One possible explanation for this observation is that VDR activators exert a positive impact on cardiovascular functions. Studies in animals with disrupted genes involved in the vitamin D signaling pathway have provided some interesting data. For example, in mice lacking VDR or CYP27B1, it was found that in addition to the expected phenotype (hypocalcemia, secondary hyperparathyroidism and osteomalacia), expression of renin or atrial natriuretic peptide was elevated. The mice also developed hypertension and cardiac hypertrophy. Gene expression profiling studies have revealed that VDR may play a role in regulating smooth-muscle-cell (SMC) proliferation, thrombosis, fibrinolysis and vessel relaxation. Paricalcitol and calcitriol are equally potent at suppressing plasminogen activator inhibitor-1 synthesis and inhibiting cellular proliferation in human coronary artery SMCs. The effect of VDR activators on the modulation of renin expression and vascular functions may be factors that contribute to reduced mortality and morbidity risk in VDR-activator-treated CKD patients. In this review, we discuss recent preclinical and clinical data regarding the role of VDR and its ligands in the cardiovascular system.


Assuntos
Calcitriol/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Ergocalciferóis/uso terapêutico , Falência Renal Crônica/tratamento farmacológico , Receptores de Calcitriol/metabolismo , Ensaios Clínicos como Assunto , Humanos , Modelos Biológicos
7.
J Steroid Biochem Mol Biol ; 98(1): 72-7, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16242929

RESUMO

Deficiency in Vitamin D and its metabolites leads to a failure in bone formation primarily caused by dysfunctional mineralization, suggesting that Vitamin D analogs might stimulate osteoblastic bone formation and mineralization. In this study, we compare the effect of selected Vitamin D analogs and active metabolite, 1alpha,25-dihydroxyvitamin D(3), 19-nor-1alpha, 25-dihydroxyvitamin D(2), and 1alpha-hydroxyvitamin D(2) or 1alpha,25-dihydroxyvitamin D(2) on bone formation and resorption. In a mouse calvariae bone primary organ culture system, all Vitamin D analogs and metabolite tested-stimulated collagen synthesis in a dose-dependent manner and 19-nor-1alpha, 25-dihydroxyvitamin D(2) was the most efficacious among three. 19-nor-1alpha, 25-dihydroxyvitamin D(2) and 1alpha,25-dihydroxyvitamin D(2) showed similar potencies and 1alpha,25-dihydroxyvitamin D(3) was less potent than others. Osteocalcin was also up-regulated in a dose-dependent manner, suggesting that the three Vitamin D analogs have the equal potencies on bone formation. 25-Hydroxyvitamin D-24-hydroxylase expression was induced in a dose-dependent manner and 19-nor-1alpha, 25-dihydroxyvitamin D(2) was less potent than other two compounds. In a mouse calvariae organ culture, all induced a net calcium release from calvariae in a dose-dependent manner, but the potency is in the order of 1alpha,25-dihydroxyvitamin D(2) congruent with1alpha,25-dihydroxyvitamin D(3)>19-nor-1alpha, 25-dihydroxyvitamin D(2). In a Vitamin D/calcium-restricted rat model, all caused an elevation in serum calcium in a dose-dependent manner. There is no significant difference between 1alpha,25-dihydroxyvitamin D(3) and 1alpha-hydroxyvitamin D(2) in potencies, but 19-nor-1alpha, 25-dihydroxyvitamin D(2) is at least 10-fold less potent than the other two compounds. Our results suggest that Vitamin D analogs have direct effects on bone resorption and formation, and 19-nor-1alpha, 25-dihydroxyvitamin D(2) may be more effective than 1alpha,25-dihydroxyvitamin D(3) and 1alpha-hydroxyvitamin D(2) on stimulating anabolic bone formation.


Assuntos
Reabsorção Óssea , Osteogênese/efeitos dos fármacos , Crânio/efeitos dos fármacos , Vitamina D/farmacologia , Animais , Calcitriol/farmacologia , Cálcio/metabolismo , Agonistas dos Canais de Cálcio/farmacologia , Ergocalciferóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Técnicas de Cultura de Órgãos , Osteocalcina/genética , Osteocalcina/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Vitamina D/análogos & derivados
8.
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
9.
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
10.
J Cardiovasc Pharmacol ; 49(4): 228-35, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17438408

RESUMO

Sirolimus (rapamycin) is an immunosuppressant used in preventing allograft rejection and in drug-eluting stents to prevent restenosis after angioplasty. Zotarolimus, an analogue of sirolimus, was designed to have a shorter in vivo half-life. Zotarolimus was found to be mechanistically similar to sirolimus in having high-affinity binding to the immunophilin FKBP12 and comparable potency for inhibiting in vitro proliferation of both human and rat T cells. Rat pharmacokinetic studies with intravenous dosing demonstrated terminal elimination half-lives of 9.4 hours and 14.0 hours for zotarolimus and sirolimus, respectively. Given orally, T1/2 values were 7.9 hours and 33.4 hours, respectively. Consistent with its shorter duration, zotarolimus showed a corresponding and statistically significant 4-fold reduction in potency for systemic immunosuppression in 3 rat disease models. Pharmacokinetic studies in cynomolgus monkey underpredicted the half-life difference between zotarolimus and sirolimus apparent from recent clinical data. In vitro inhibition of human coronary artery smooth muscle cell proliferation by zotarolimus was comparable to sirolimus. Drug-eluting stents for local delivery of zotarolimus to the vessel wall of coronary arteries are in clinical development. The pharmacological profile of zotarolimus suggests it may be advantageous for preventing restenosis with a reduced potential for causing systemic immunosuppression or other side effects.


Assuntos
Proliferação de Células/efeitos dos fármacos , Vasos Coronários/citologia , Rejeição de Enxerto/prevenção & controle , Imunossupressores/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Sirolimo/análogos & derivados , Animais , Animais Recém-Nascidos , Ligação Competitiva/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipersensibilidade a Drogas/etiologia , Hipersensibilidade a Drogas/prevenção & controle , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/prevenção & controle , Meia-Vida , Transplante de Coração , Humanos , Hipersensibilidade Tardia/induzido quimicamente , Hipersensibilidade Tardia/prevenção & controle , Imunossupressores/efeitos adversos , Imunossupressores/sangue , Imunossupressores/farmacocinética , Concentração Inibidora 50 , Teste de Cultura Mista de Linfócitos , Masculino , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Sirolimo/efeitos adversos , Sirolimo/sangue , Sirolimo/farmacocinética , Sirolimo/farmacologia , Linfócitos T/efeitos dos fármacos , Proteína 1A de Ligação a Tacrolimo/efeitos dos fármacos
11.
Neurourol Urodyn ; 22(2): 147-55, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12579633

RESUMO

AIMS: To compare in vivo the efficacy, potency, and bladder-vascular selectivity of ATP-sensitive potassium channel openers (KCOs), YM934 and (-)-cromakalim to a muscarinic antagonist, tolterodine in a novel partial outlet obstructed pig model. METHODS: Partially obstructed female Landrace pigs were implanted with telemetry transmitters to allow the continuous measurement of intravesical, abdominal and arterial pressures. A subcutaneous port catheter was used to adjust bladder volume. Bladder and arterial pressure were simultaneously monitored under isoflurane anesthesia before and after increasing i.v. doses of test compounds. RESULTS: Under anesthesia, voiding was completely inhibited, but spontaneous, nonvoiding bladder contractions were observed with mean amplitude of 16 +/- 1 cm H(2)O, duration of 35 +/- 2 seconds, and intercontraction interval of 43 +/- 4 seconds (n = 25). YM934 and (-)-cromakalim both caused dose-dependent decreases in bladder contraction area under the curve (AUC) with effective doses to inhibit AUC by 35% of 3.6 and 14.9 nmol/kg, i.v., respectively. However, concomitant reductions in mean arterial pressure of 12 and 13% were also observed. Tolterodine did not inhibit spontaneous bladder contractions at doses up to 100 nmol/kg, i.v. corresponding to plasma concentrations up to 41 ng/mL. CONCLUSIONS: The superior efficacy of KCOs to inhibit spontaneous bladder contractions relative to tolterodine support the hypothesis that KCOs may provide an alternate therapeutic mechanism to treat symptoms of overactive bladder if bladder-vascular selectivity can be sufficiently improved. The minimally invasive model described herein appears useful in the preclinical evaluation of potential therapeutics targeted to treat the overactive bladder.


Assuntos
Compostos Benzidrílicos/farmacologia , Cresóis/farmacologia , Óxidos N-Cíclicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Oxazinas/farmacologia , Fenilpropanolamina , Canais de Potássio/metabolismo , Obstrução do Colo da Bexiga Urinária/tratamento farmacológico , Trifosfato de Adenosina/metabolismo , Animais , Benzoxazinas , Cromakalim/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Ativação do Canal Iônico/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Parassimpatolíticos/farmacologia , Sus scrofa , Tartarato de Tolterodina , Bexiga Urinária/fisiologia , Obstrução do Colo da Bexiga Urinária/fisiopatologia , Urodinâmica/efeitos dos fármacos
12.
J Pharmacol Exp Ther ; 303(1): 387-94, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12235275

RESUMO

ATP-sensitive potassium (K(ATP)) channel openers (KCOs) have been shown to inhibit spontaneous myogenic contractile activity of the urinary bladder, a mechanism hypothesized to underlie detrusor instability and symptoms of overactive bladder. However, the therapeutic utility of KCOs has been limited by a lack of differentiation of bladder versus vascular effects. In this study, we evaluated the in vivo potency and bladder selectivity of (-)-(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637), a novel dihydropyridine KCO, in a pig model of detrusor instability secondary to partial bladder outlet obstruction. For comparison, we profiled two KCOs, ((R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzonitrile (WAY-133537) and (S)-N-(4-benzoylphenyl)-3,3,3-trifluro-2-hydroxy-2-methyl-propionamide (ZD6169), reported previously to have improved bladder selectivity in vivo and a calcium channel blocker, nifedipine. Effective doses of A-278637, WAY-133537, ZD6169, and nifedipine to inhibit unstable contraction area under the curve by 35% and to decrease mean arterial pressure by 10% were 4.2 and 12, 109 and 51, 661 and 371, and 136 and 30 nmol/kg i.v., yielding corresponding bladder selectivity ratios of 3, 0.5, 0.6, and 0.2. Therefore, A-278637 was approximately 5- to 6-fold more bladder-selective than the other KCOs and 15-fold more selective than nifedipine, the latter approximately 4.5-fold vascular-selective. The potency of KCOs to inhibit unstable contraction in vivo was accurately predicted by their potency to inhibit spontaneous contractile activity of pig detrusor strips in vitro. These results indicate that A-278637, with enhanced potency and bladder selectivity compared with the other compounds evaluated, could serve as a useful tool in the investigation of smooth muscle K(ATP) channel openers as novel therapeutic agents for the treatment of overactive bladder.


Assuntos
Óxidos S-Cíclicos/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/fisiologia , Canais de Potássio/fisiologia , Quinolonas/farmacologia , Bexiga Urinária/fisiologia , Transportadores de Cassetes de Ligação de ATP , Amidas/farmacologia , Animais , Benzofenonas/farmacologia , Ciclobutanos/farmacologia , Ativação do Canal Iônico/efeitos dos fármacos , Ativação do Canal Iônico/fisiologia , Canais KATP , Contração Muscular/fisiologia , Músculo Liso/efeitos dos fármacos , Nifedipino/farmacologia , Nitrilas/farmacologia , Canais de Potássio/efeitos dos fármacos , Canais de Potássio Corretores do Fluxo de Internalização , Suínos
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