RESUMEN
BACKGROUND: The design, medicinal chemistry, pharmacokinetics and development of the highly selective α2-adrenoceptor antagonist fluparoxan are reviewed. METHOD: The drug's activity and selectivity in vitro, its efficacy in animals and its excellent oral pharmacokinetics and central α2-adrenoceptor antagonist activity in man, are evaluated as well as its ability to increase extracellular levels of noradrenaline, dopamine and acetylcholine in vivo. CONCLUSION: Furthermore, its potential for the treatment of central neurodegenerative diseases is highlighted, in particular its improvement of cognitive dysfunction in schizophrenia and in models of Alzheimer's disease.
Asunto(s)
Adrenérgicos/farmacología , Sistema Nervioso Central/efectos de los fármacos , Disfunción Cognitiva/tratamiento farmacológico , Descubrimiento de Drogas , Enfermedades Neurodegenerativas/tratamiento farmacológico , Piperoxano/análogos & derivados , Pirroles/farmacología , Adrenérgicos/síntesis química , Adrenérgicos/química , Animales , Sistema Nervioso Central/patología , Disfunción Cognitiva/patología , Humanos , Enfermedades Neurodegenerativas/patología , Piperoxano/síntesis química , Piperoxano/química , Piperoxano/farmacología , Pirroles/síntesis química , Pirroles/químicaRESUMEN
Locus coeruleus degeneration and reduced central noradrenaline content is an early feature of Alzheimer's disease. In transgenic mouse models of Alzheimer's disease-like pathology, lesioning the locus coeruleus exacerbates ß-amyloid (Aß) pathology, neuroinflammation and memory deficits. Here we aimed to determine whether chronic treatment with the α(2)-adrenoceptor antagonist fluparoxan, that enhances noradrenaline release, can prevent the onset of Alzheimer's-like pathology and memory deficits in APP/PS1 transgenic mice (TASTPM). Fluparoxan (1mg/kg/day) was administered to TASTPM and wild type mice from 4 to 8 months of age. Memory was assessed at 4 and 8 months of age using the Morris water maze and contextual fear conditioning and at monthly intervals during the duration of treatment using the object recognition and spontaneous alternation task. Aß plaque load and astrocytosis were measured at 4 and 8 months of age by immunohistochemistry. Fluparoxan treatment prevented age-related spatial working memory deficits in the spontaneous alternation task but not spatial reference memory deficits in the Morris water maze. Aß plaque load and astrocytosis were unaltered by fluparoxan treatment in TASTPM mice. The findings suggest that fluparoxan treatment selectively prevent the decline of forms of memory where noradrenaline plays an integral role and that this beneficial effect is not due to altered Aß plaque pathology or astrocytosis.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Envejecimiento , Péptidos beta-Amiloides/biosíntesis , Gliosis/tratamiento farmacológico , Trastornos de la Memoria/prevención & control , Piperoxano/análogos & derivados , Placa Amiloide/tratamiento farmacológico , Pirroles/administración & dosificación , Envejecimiento/genética , Envejecimiento/metabolismo , Envejecimiento/patología , Péptidos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/biosíntesis , Precursor de Proteína beta-Amiloide/genética , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Astrocitos/patología , Gliosis/genética , Gliosis/metabolismo , Humanos , Estudios Longitudinales , Trastornos de la Memoria/genética , Trastornos de la Memoria/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Piperoxano/administración & dosificación , Placa Amiloide/genética , Placa Amiloide/metabolismo , Presenilina-1/biosíntesis , Presenilina-1/genética , Receptores Adrenérgicos alfa 2/fisiología , Resultado del TratamientoRESUMEN
Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbine, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. Yohimbine displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to yohimbine, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. Yohimbine likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 2 , Lóbulo Frontal/fisiología , Piperoxano/análogos & derivados , Pirroles/farmacología , Receptores de Dopamina D2/fisiología , Receptores de Serotonina/fisiología , Transmisión Sináptica/fisiología , Yohimbina/farmacología , Antagonistas de Receptores Adrenérgicos alfa 2 , Antagonistas Adrenérgicos alfa/farmacología , Animales , Antidepresivos/farmacología , Temperatura Corporal/efectos de los fármacos , Lóbulo Frontal/efectos de los fármacos , Cobayas , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Humanos , Ratones , Neuronas/efectos de los fármacos , Neuronas/fisiología , Piperoxano/farmacología , Ratas , Receptor de Serotonina 5-HT1B , Receptor de Serotonina 5-HT1D , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D3 , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina 5-HT1 , Porcinos , Transmisión Sináptica/efectos de los fármacosRESUMEN
1. Fluparoxan is an alpha 2-adrenoceptor antagonist that has a relatively planar, tricyclic structure and was considered a potential substrate and inducer of cytochrome P4501A (CYP1A) enzymes. 2. Structure-activity analysis indicated some potential for CYP1A interaction, although its greater log P and molecular depth, compared with many CYP1A inducers, suggested fluparoxan would be a weak ligand for the aryl hydrocarbon (Ah) receptor and only a weak inducer. 3. In vitro, fluparoxan showed little affinity for the CYP1A enzymes. The compound was not metabolized by human CYP1A1 or 1A2 heterologously expressed in yeast and its rate of metabolism in rat and human microsomes was unaffected by the addition of the 1A inhibitor alpha-naphthoflavone. Furthermore, Ki's for fluparoxan against EROD activity were > 4000-fold higher than those of alpha-naphthoflavone. 4. In vivo, however, fluparoxan did show some capacity for CYP1A induction. In rat, hepatic EROD activity increased approximately 40-fold with seven once-daily oral doses of fluparoxan (50 mg/kg, solution), and immunoblotting studies confirmed induction of CYP1A2, though not of 1A1. In man, administration of 11 twice-daily oral doses of fluparoxan (8 mg tablet) produced some reduction in plasma levels of orally administered phenacetin and in the ratio of phenacetin AUC/urinary paracetamol, consistent with increased O-deethylation.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 2 , Antagonistas Adrenérgicos alfa/farmacología , Citocromo P-450 CYP1A1/biosíntesis , Piperoxano/análogos & derivados , Pirroles/farmacología , Adolescente , Adulto , Animales , Citocromo P-450 CYP1A2/biosíntesis , Inducción Enzimática , Humanos , Masculino , Microsomas Hepáticos/metabolismo , Estructura Molecular , Piperoxano/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
We have previously shown that the release of acetylcholine (ACh) in the medial prefrontal cortex of the conscious rat, as measured by microdialysis, is increased following intraperitoneal injection of the selective alpha 2-adrenoceptor antagonist (+)-efaroxan. To characterize further the receptor pharmacology of this response, the effects of other selective alpha 2-adrenoceptor ligands were examined. The alpha 2-adrenoceptor antagonists idazoxan (2.5 and 20 mg/kg), atipamezole (2.5 mg/kg), and fluparoxan (10 mg/kg) increased ACh outflow by up to 250-325% of basal levels over a 3-h period following intraperitoneal injection. The alpha 2-adrenoceptor agonists UK-14304 (2.5 mg/kg) and guanabenz (2.5 mg/kg) reduced ACh outflow by 80 and 60%, respectively. Clonidine (0.00063-0.16 mg/kg) had no significant depressant effect and at 2.5 mg/kg increased ACh outflow to 233% of basal levels. These results indicate a modulatory role for alpha 2-adrenoceptors on the release of ACh in the rat prefrontal cortex in vivo. Based on the facilitatory effects produced by the antagonists alone, this alpha 2-adrenoceptor modulation appears to be tonic and inhibitory. The ability of alpha 2-adrenoceptor antagonists to enhance ACh outflow suggests a therapeutic usefulness in disorders where cortical ACh release deficits have been implicated.
Asunto(s)
Acetilcolina/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2 , Antagonistas de Receptores Adrenérgicos alfa 2 , Corteza Prefrontal/metabolismo , Agonistas alfa-Adrenérgicos/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Animales , Tartrato de Brimonidina , Clonidina/farmacología , Guanabenzo/farmacología , Idazoxan/farmacología , Imidazoles/farmacología , Masculino , Microdiálisis , Piperoxano/análogos & derivados , Piperoxano/farmacología , Corteza Prefrontal/química , Pirroles/farmacología , Quinoxalinas/farmacología , Ratas , Ratas Sprague-DawleyAsunto(s)
Electroforesis/métodos , Antagonistas Adrenérgicos alfa/aislamiento & purificación , Acción Capilar , Piperoxano/análogos & derivados , Piperoxano/aislamiento & purificación , Pirroles/aislamiento & purificación , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , EstereoisomerismoRESUMEN
A novel series of tetrahydrobenzodioxinopyrroles has been identified as potent and selective alpha 2-adrenoceptor antagonists. Convergent syntheses have been developed that allowed the preparation of analogues and their enantiomers. A compound of particular interest is the 5-fluoro substituted analogue (fluparoxan).
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 2 , Antagonistas Adrenérgicos alfa/síntesis química , Antagonistas Adrenérgicos alfa/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Antagonistas Adrenérgicos alfa/química , Animales , Técnicas In Vitro , Masculino , Ratones , Estructura Molecular , Piperoxano/análogos & derivados , Piperoxano/síntesis química , Piperoxano/química , Piperoxano/farmacología , Pirroles/química , Ratas , EstereoisomerismoRESUMEN
Urinary excretion of neopterins (N) and biopterins (B) was measured in 48 patients with depression before and after treatment with placebo, antidepressants, or electroconvulsive therapy (ECT), and in 26 healthy control subjects. Patients prior to and after treatment had a significantly greater neopterin/biopterin (N:B) ratio than control subjects. There was a significant correlation between N:B ratios and the severity of depression and plasma cortisol. As a raised N:B ratio implies failure to convert neopterin to biopterin, it is possible that reduced availability of tetrahydrobiopterin, the essential cofactor for the formation of noradrenaline, serotonin and dopamine, may exert rate-limiting control over the synthesis of monoamines implicated in the pathogenesis of depressive illness.
Asunto(s)
Antidepresivos/uso terapéutico , Biopterinas/análogos & derivados , Biopterinas/orina , Trastorno Depresivo/terapia , Terapia Electroconvulsiva , Adulto , Anciano , Amitriptilina/efectos adversos , Amitriptilina/uso terapéutico , Antidepresivos/efectos adversos , Ensayos Clínicos como Asunto , Trastorno Depresivo/psicología , Trastorno Depresivo/orina , Femenino , Humanos , Hidrocortisona/sangre , Masculino , Persona de Mediana Edad , Neopterin , Piperoxano/efectos adversos , Piperoxano/análogos & derivados , Piperoxano/uso terapéutico , Pirroles/efectos adversos , Pirroles/uso terapéutico , Pirrolidinonas/efectos adversos , Pirrolidinonas/uso terapéutico , Valores de Referencia , RolipramRESUMEN
1. The effects of fluparoxan, an alpha 2-adrenoceptor antagonist, on the pharmacodynamic changes induced by clonidine were investigated in this placebo-controlled, double-blind, two-period, cross-over study in 16 healthy male volunteers (aged 19 to 44 years). 2. Subjects received either fluparoxan or placebo, twice-daily for 5 1/2 days (11 doses). One hour after the first and last dose of each treatment period, clonidine (200 micrograms) was infused intravenously over 5 min. 3. Indices of clonidine-mediated pharmacodynamic responses (growth hormone secretion, bradycardia, hypotension, xerostomia and sedation) were taken before and after clonidine infusion. Growth hormone secretion was assessed by quantifying serum growth hormone concentrations; sedation was assessed by both visual analogue scales (VAS) and by a visual psychomotor response meter, measuring critical flicker fusion (CFF). 4. The majority of subjects reported minor adverse events such as lethargy, headache and dry mouth following clonidine infusion. All adverse events were likely to be related to clonidine, as they occurred consistently between treatment groups. Fluparoxan has, however, in previous studies been reported to cause headache and light-headedness. 5. Prior to the clonidine infusion, fluparoxan caused small but statistically significant increases in systolic blood pressure (4 mm Hg) and salivary flow (approximately 30%) after both single and repeated doses. A small increase in heart rate (2 beats min-1) was seen after a single dose which was also statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Antagonistas Adrenérgicos alfa/farmacología , Antidepresivos/farmacología , Presión Sanguínea/efectos de los fármacos , Clonidina/antagonistas & inhibidores , Frecuencia Cardíaca/efectos de los fármacos , Piperoxano/análogos & derivados , Pirroles/farmacología , Administración Oral , Antagonistas Adrenérgicos alfa/administración & dosificación , Adulto , Antidepresivos/administración & dosificación , Bradicardia/inducido químicamente , Clonidina/administración & dosificación , Estudios Cruzados , Método Doble Ciego , Hormona del Crecimiento/metabolismo , Humanos , Hipotensión/inducido químicamente , Infusiones Intravenosas , Masculino , Piperoxano/administración & dosificación , Piperoxano/farmacología , Desempeño Psicomotor/efectos de los fármacos , Pirroles/administración & dosificación , Xerostomía/inducido químicamenteAsunto(s)
Inhibidores de Adenilato Ciclasa , Amitriptilina/uso terapéutico , Antidepresivos/uso terapéutico , Trastorno Depresivo/tratamiento farmacológico , Piperoxano/análogos & derivados , Pirroles/uso terapéutico , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Adulto , Anciano , Plaquetas/efectos de los fármacos , Plaquetas/enzimología , Trastorno Depresivo/enzimología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piperoxano/uso terapéuticoRESUMEN
1. Achiral reverse-phase h.p.l.c. with semi-automated post-column fraction collection and solid-phase sample reconcentration, has been applied as the purification procedure during the enantiomeric quantification of two widely differing experimental drugs; an HMG-CoA reductase inhibitor (I) and an alpha 2-adrenoceptor antagonist (II). 2. The robust and specific achiral methodologies were available prior to the need for chiral analyses and recovery of drug from the fractions provided clean samples from a variety of biological matrices, without the need to develop compatible achiral/chiral mobile phases. 3. Compared with direct chiral chromatography of plasma extracts, this approach decreased the potential for metabolites and endogenous components to interfere or impair the performance of the chiral stationary phase. 4. The availability of quantitative data from achiral analysis of samples negated the need for internal standardization of the chiral analyses, helped confirm assay specificity and provided potential to determine enantiomeric ratios where only one isomer could be accurately measured. 5. Routine enantiomeric analyses were successfully carried out on samples taken from animals dosed orally with the racemic drugs, providing important data on the possible levels of exposure to individual enantiomers during toxicity testing.
Asunto(s)
Imidazoles/aislamiento & purificación , Piperoxano/análogos & derivados , Pirroles/aislamiento & purificación , Animales , Calibración , Cromatografía Líquida de Alta Presión/métodos , Perros , Femenino , Hidroximetilglutaril-CoA Sintasa/antagonistas & inhibidores , Imidazoles/farmacocinética , Imidazoles/toxicidad , Masculino , Piperoxano/aislamiento & purificación , Piperoxano/farmacocinética , Piperoxano/toxicidad , Pirroles/farmacocinética , Pirroles/toxicidad , Ratas , EstereoisomerismoRESUMEN
1. This paper describes the pharmacology of the novel alpha 2-adrenoceptor antagonist fluparoxan (GR 50360) which is currently being studied clinically as a potential anti-depressant. Idazoxan and yohimbine were included in many studies for comparison. 2. In the rat isolated, field-stimulated vas deferens and the guinea-pig isolated, field-stimulated ileum preparations, fluparoxan was a reversible competitive antagonist of the inhibitory responses to the alpha 2-adrenoceptor agonist UK-14304 with pKB values of 7.87 and 7.89 respectively. In the rat isolated anococcygeus muscle, fluparoxan was a much weaker competitive antagonist of the contractile response to the alpha 1-adrenoceptor agonist phenylephrine with a pKB of 4.45 giving an alpha 2: alpha 1-adrenoceptor selectivity ratio of greater than 2500. 3. In the conscious mouse, fluparoxan (0.2-3.0 mg kg-1) was effective by the oral route and of similar potency to idazoxan in preventing clonidine-induced hypothermia and antinociception. In the rat, UK-14304-induced hypothermia (ED50 = 1.4 mg kg-1, p.o. or 0.5 mg kg-1, i.v.) and rotarod impairment (ED50 = 1.1 mg kg-1 p.o. or 1.3 mg kg-1, i.v.) were antagonized by fluparoxan. Fluparoxan, 0.67-6 mg kg-1, p.o., also prevented UK-14304-induced sedation and bradycardia in the dog. 4. In specificity studies fluparoxan had low or no affinity for a wide range of neurotransmitter receptor sites at concentrations up to at least 1 x 10(-5) M. It displayed weak affinity for 5-HT1A (pIC50 = 5.9) and 5-HT1B (pKi = 5.5) binding sites in rat brain. 5. We conclude that fluparoxan is a highly selective and potent alpha 2-adrenoceptor antagonist. The density of rat brain [3H]-dihydroalprenolol binding sites was reduced by 26% when fluparoxan was administered chronically for 6 days at a dose of 12 mg kg- 1 orally twice daily. The down-regulation of beta-adrenoceptors by fluparoxan is consistent with its antidepressant potential.
Asunto(s)
Antagonistas Adrenérgicos alfa/farmacología , Piperoxano/análogos & derivados , Pirroles/farmacología , Agonistas alfa-Adrenérgicos/farmacología , Analgésicos/antagonistas & inhibidores , Animales , Aorta/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Tartrato de Brimonidina , Clonidina/antagonistas & inhibidores , Cobayas , Frecuencia Cardíaca/efectos de los fármacos , Íleon/efectos de los fármacos , Técnicas In Vitro , Masculino , Músculo Liso/efectos de los fármacos , Norepinefrina/metabolismo , Piperoxano/farmacología , Equilibrio Postural/efectos de los fármacos , Quinoxalinas/antagonistas & inhibidores , Conejos , Ratas , Ratas Endogámicas , Receptores Adrenérgicos alfa/efectos de los fármacos , Receptores Adrenérgicos alfa/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores Histamínicos/metabolismo , Receptores Muscarínicos/metabolismo , Receptores de Serotonina/metabolismo , Conducto Deferente/efectos de los fármacosAsunto(s)
Antidepresivos/sangre , Cromatografía de Gases , Piperidinas/sangre , Piperoxano/sangre , Pirroles/sangre , Antidepresivos/farmacocinética , Cromatografía de Gases/estadística & datos numéricos , Semivida , Humanos , Estructura Molecular , Piperoxano/análogos & derivados , Piperoxano/farmacocinética , Pirroles/farmacocinética , Control de CalidadRESUMEN
The synthesis and in vitro alpha- and beta-adrenergic blocking potency of 1-[1-(2-benzodiaxanylmethyl)-4-piperidyl]amino-3-(1-naphthoxy-2-pr opanol (I) are described. Thus, N-benzyl-4piperidone was protected and debenzylated to the carbamate (V), which upon alkaline hydrolysis and acylation gave benzodioxanic amide (IX). Reduction of the amide group, deprotection of the ketone function of (X), and reductive amination gave the 4-aminopiperidine (XIII), which was finally condensed with the appropriate epoxide to yield the aminopropanol (I). Compound (I) is formally derived from a combination of piperoxan (II) and propranolol (III), and was approximately 10 times less potent than each one of these drugs, as an alpha- and beta-adrenergic blocker respectively.
Asunto(s)
Antagonistas Adrenérgicos alfa/síntesis química , Antagonistas Adrenérgicos beta/síntesis química , Piperoxano/análogos & derivados , Propranolol/análogos & derivados , Animales , Aorta Torácica/efectos de los fármacos , Fenómenos Químicos , Química , Femenino , Cobayas , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Piperoxano/síntesis química , Propranolol/síntesis química , Ratas , Tráquea/efectos de los fármacos , Conducto Deferente/efectos de los fármacosRESUMEN
Three piperoxan analogues, derived from the opening of the benzodioxane ring and/or replacement of the oxygen atom with the less polar sulfur, were synthesized. The decrease of the alpha-blocking activity found for these compounds showed that the binding site of benzodioxane-like compounds does not accept the substitution with less polar groups.
Asunto(s)
Antagonistas Adrenérgicos alfa/síntesis química , Piperidinas/farmacología , Piperoxano/farmacología , Animales , Fenómenos Químicos , Química , Estimulación Eléctrica , Técnicas In Vitro , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Piperoxano/análogos & derivados , Piperoxano/síntesis química , Ratas , Receptores Adrenérgicos alfa/efectos de los fármacos , Relación Estructura-Actividad , Sinapsis/efectos de los fármacosRESUMEN
The alpha-adrenoceptors blocking effect of (N-piperidinomethyl)-2-chromanne was studied in vivo and in vitro in the rat. In the pithed rat, (N-piperidinomethyl)-2-chromanne (1 mg/kg i.v.) antagonized the pressor effects induced by alpha agonists. (N-piperidinomethyl)-2-chromanne competitively antagonized the pressor effects of M7 (alpha 2-agonist) and cirazoline (alpha 1-agonist). (N-piperidinomethyl)-2-chromanne antagonized the inhibitory effects of clonidine on presynaptic alpha 2-receptors in stimulated pithed rats. On the vas deferens of the rat (N-piperidinomethyl)-2-chromanne antagonized the inhibitory effects of clonidine on the twitch response produced by electrical stimulation and also the contractions induced by phenylephrine. This derivate appears to be an alpha 1 and alpha 2 blocking agent.
Asunto(s)
Piperidinas/farmacología , Piperoxano/farmacología , Receptores Adrenérgicos alfa/efectos de los fármacos , Receptores de Neurotransmisores/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Clonidina/farmacología , Estado de Descerebración , Estimulación Eléctrica , Imidazoles/farmacología , Técnicas In Vitro , Masculino , Músculo Liso/efectos de los fármacos , Piperoxano/análogos & derivados , Ratas , Ratas Endogámicas , Conducto Deferente/efectos de los fármacosAsunto(s)
Antagonistas Adrenérgicos alfa/farmacología , Dioxanos/farmacología , Dioxinas/farmacología , Piperidinas/farmacología , Piperoxano/farmacología , Antagonistas Adrenérgicos alfa/síntesis química , Antagonistas Adrenérgicos alfa/toxicidad , Animales , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Gatos , Dioxanos/síntesis química , Dioxanos/toxicidad , Dosificación Letal Mediana , Masculino , Ratones , Norepinefrina/antagonistas & inhibidores , Piperoxano/análogos & derivados , Piperoxano/síntesis química , Piperoxano/toxicidad , Conejos , Ratas , Receptores Adrenérgicos alfa/efectos de los fármacos , Respiración/efectos de los fármacos , Tolazolina/farmacologíaRESUMEN
A series of benzodioxane derivatives, structurally related to WB 4101 and piperoxan as well as prazosin and its two analogues UK-18,596 and UK-33,274, was studied with respect to their affinity for alpha 1-and alpha 2-adrenoceptors identified by 3H-prazosin (specific activity 33 Ci/mmol) and 3H-clonidine (specific activity 26.7 Ci/mmol), respectively, in isolated rat brain membranes. The structural variations made in these molecules gave rise to pronounced differences in affinity for alpha 1-adrenoceptors, whereas their binding affinity for alpha 2-adrenoceptors only slightly varied. Apart from piperoxan and its analogues, which showed some preference for alpha 2-adrenergic binding sites, all benzodioxane-like structures displayed a general selectivity for the alpha 1-adrenoreceptor sites labeled with 3H-prazosin. The drugs were 5-50 times more potent in inhibiting 3H-prazosin than 3H-clonidine from their specific binding sites in rat brain membranes. The highest alpha 1 selectivity was found for prazosin and UK-33,274. Within the present series of WB 4101-related benzodioxane compounds, the affinity for alpha 1-adrenoceptors is greatly reduced by alkyl substitution at the secondary amino nitrogen in the side chain. Ortho substitution of the phenyl moiety with methoxy increased affinity as did hydroxy at the para position. The side chain oxygen atom can be deleted or substituted by methylene without great loss in 3H-prazosin displacing effectiveness. The affinity for alpha 1-adrenoceptors was profoundly influenced by the configuration of the molecule. Upon introducing a second chiral center through a methyl group, the two resulting racemates differ 10-fold in activity and selectivity towards alpha 1-adrenoceptors. One of these racemates was even slightly more selective than WB 4101 itself. The selectivity of the drugs to bind to alpha 1-and alpha 2-adrenoceptors corresponded well with their in vivo selectivity to antagonize alpha 1- and alpha 2-adrenoceptor-mediated vasoconstriction in pithed normotensive rats. It is suggested that a systematic study of the structure-affinity relationship in benzodioxane antagonists may provide potent and selective blocking drugs of alpha 1-adrenoceptors.
Asunto(s)
Antagonistas Adrenérgicos alfa/metabolismo , Piperidinas/metabolismo , Piperoxano/metabolismo , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos/metabolismo , Animales , Unión Competitiva , Presión Sanguínea/efectos de los fármacos , Encéfalo/metabolismo , Clonidina/metabolismo , Técnicas In Vitro , Masculino , Membranas/metabolismo , Piperoxano/análogos & derivados , Piperoxano/farmacología , Prazosina/antagonistas & inhibidores , Ratas , Ratas EndogámicasRESUMEN
Hypotensive activities were determined of some derivatives of erythro 1-(1-[2-(1,4-benzodioxane-2-yl)-2-hydroxyethyl]-4-piperidyl)-2-benzimidazolinone (R 28935) following intravenous administration to anaesthetized normotensive rats. Introduction of chlorine into the benzimidazolinone part of R 28935 negatively influenced the hypotensive potency as did opening of the dioxane ring. An appropriate substituent restored the hypotensive effectiveness of the "opened" structures. In general, the compounds were weak inhibitors of the specific binding of (3H)-prazosin (alpha 1-adrenoceptors), (3H)-clonidine (alpha 2-adrenoceptors) and (3H)-dihydromorphine (opiate-receptors) to rat brain membranes. The relative order of affinity for either receptor did not correspond with that of the hypotensive activity. Previous (-15 min) intravenous treatment with phentolamine (0.2 mg/kg) abolished the depressor effect of prazosin and diminished that of the threo form R 29814 as well as of all "opened" congeners, but did not significantly reduce the hypotensive response to R 28935 and the other erythro structures. It is concluded that neither alpha 1- and alpha 2- nor opiate-receptors are involved as the primary targets for R 28935 and its congeneric drugs to induce hypotension. The exact mechanism of action remains therefore unsolved. Erythro R 28935 and the other racemic erythro mixtures are centrally acting hypotensive agents. A peripheral alpha-sympatholytic component may contribute to the overall depressor effect of threo R 29814 and the "opened" derivatives.