RESUMEN
A series of cis- and trans-fused hexahydroindeno[2,1-c]pyridines have been prepared and evaluated for affinity and selectivity at the 5-HT1A subtype of the serotonin receptor. Using molecular modeling studies we predicted that the 5-methoxy-trans-fused members of this class would exhibit affinity for this site. In agreement with these predictions, trans-5-methoxy-N-propyl-2,3,4,4a,9,-9a-hexahydro-1H-indeno[2,1-c]pyridi ne (6a) demonstrated moderate affinity and high selectivity for the 5-HT1A binding site, whereas the cis-fused isomer 5a demonstrated virtually no affinity at this site. Additional trans-fused analogs from this series, where the nitrogen was substituted with a variety of alkylene imide containing appendages, demonstrated high (0.60-51 nM) affinity and excellent selectivity for the 5-HT1A site. Certain of these analogs, independent of ring-fusion stereochemistry, also demonstrated high affinity for the 5-HT2 binding site.
Asunto(s)
Piridinas/síntesis química , Receptores de Serotonina/metabolismo , Sitios de Unión , Unión Competitiva , Diseño de Fármacos , Indenos/síntesis química , Indenos/metabolismo , Ketanserina/metabolismo , Espectroscopía de Resonancia Magnética , Conformación Molecular , Estructura Molecular , Piridinas/metabolismo , Serotonina/metabolismo , Relación Estructura-ActividadRESUMEN
A number of quaternary salts of trans-4-(beta-1-naphthylvinyl)pyridine (NVP) were synthesized and evaluated as inhibitors of the enzymes choline acetyltransferase (ChAT) and acetylcholinesterase (AChE). Structural variations in the side arm attached to the pyridine nitrogen atom demonstrate that an inductive effect is small but significant for activity. Inhibition of ChAT by alkylated derivatives decreases when electron-withdrawing groups are placed in the side chain. Substitution of a methyl group on the pyridine ring only slightly affects activities toward ChAT and AChE. When the pyridinium moiety is replaced by an imidazolium ring, no ChAT inhibition was observed. The imidazolium compound, however, was a weak inhibitor of AChE. For design of affinity columns for purification of ChAT, the data also supports the use of long chain alkylated amide derivatives of NVP.
Asunto(s)
Colina O-Acetiltransferasa/antagonistas & inhibidores , Piridinas/síntesis química , Animales , Encéfalo/enzimología , Indicadores y Reactivos , Naftoles/síntesis química , Naftoles/farmacología , Piridinas/farmacología , Ratas , Relación Estructura-Actividad , Compuestos de Vinilo/síntesis química , Compuestos de Vinilo/farmacologíaRESUMEN
A series of modifications to positions 1, 2, and 4 of the tetralin ring of 5,6-dihydroxy-1-(2-imidazolinyl)tetralin (1, A-54741) succeeded in improving the separation of the potent alpha 1 and alpha 2 adrenergic agonism observed for the parent compound 1. In particular 5,6-dihydroxy-4,4-dimethyl-1-(2-imidazolinyl)tetralin (7) was found to be a specific alpha 1 adrenergic agonist, and 7,8-dihydroxy-4-(2-imidazolinyl)chroman (2) was found to have improved alpha 2 adrenergic agonistic selectivity relative to the parent compound 1.
Asunto(s)
Simpatomiméticos/síntesis química , Animales , Aorta/efectos de los fármacos , Perros , Relación Dosis-Respuesta a Droga , Femenino , Conformación Molecular , Norepinefrina/metabolismo , Fenoxibenzamina/farmacología , Prazosina/metabolismo , Conejos , Receptores Adrenérgicos alfa/metabolismo , Relación Estructura-Actividad , Simpatomiméticos/farmacologíaRESUMEN
The synthesis of a series of 1-(aminomethyl)phthalans 1b is reported. The radioligand binding to alpha 1- and alpha 2-receptors and the in vitro pharmacology in alpha 1 (rabbit aorta) and alpha 2 (phenoxybenzamine-pretreated dog saphenous vein) tissues were determined and were compared to the activity of the corresponding 1-(aminomethyl)indans. The activity of this series of phthalans was found to be consistent with the electrostatic repulsion hypothesis that was used to design the parent indan (ERBCOP) compounds. The effect of the phthalan ring oxygenation was to somewhat improve alpha 1-receptor potency relative to the 6-ERBCOP indans without having a general effect on the alpha 2-receptor potency. We conclude from the overall pattern of activity that while the norepinephrine type beta-hydroxyl group may be beneficial for binding to the alpha 1-adrenoceptor, it is not required for strong binding to or full stimulation of the alpha 2-adrenergic receptor, provided that the conformational mobility associated with the phenylethylamine is restricted and maintained in a favorable conformation for receptor interaction.
Asunto(s)
Agonistas alfa-Adrenérgicos/síntesis química , Benzofuranos/síntesis química , Receptores Adrenérgicos alfa/metabolismo , Animales , Benzofuranos/farmacología , Encéfalo/metabolismo , Perros , Femenino , Técnicas In Vitro , Indicadores y Reactivos , Cinética , Hígado/metabolismo , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Metilaminas/síntesis química , Metilaminas/farmacología , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Conejos , Ratas , Ratas Endogámicas , Receptores Adrenérgicos alfa/efectos de los fármacos , Espectrofotometría Infrarroja , Relación Estructura-ActividadRESUMEN
The synthesis and pharmacology of 2-(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthyl)imidazoline (A-54741, 4), a very potent alpha-adrenergic agonist, are described. The change in biological activity resulting from variation of the carbocyclic ring size of 4 from four through seven members (2-5) is presented, as well as an explanation that accounts for this change in activity by considering the "exactness of fit" of these compounds to both the alpha 1- and alpha 2-adrenergic receptors. Compound 4 was found in vitro to be a full agonist with greater potency at the alpha 2 receptor (ED50 norepinephrine (NE)/ED50 4 = 188 +/- 22) than at the alpha 1 receptor (ED50 NE/ED50 4 = 13 +/- 2).
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Imidazoles/farmacología , Receptores Adrenérgicos alfa/efectos de los fármacos , Agonistas alfa-Adrenérgicos/síntesis química , Animales , Perros , Relación Dosis-Respuesta a Droga , Femenino , Imidazoles/síntesis química , Técnicas In Vitro , Masculino , Conformación Molecular , Conejos , Ratas , Ratas Endogámicas , Relación Estructura-ActividadRESUMEN
(+/-)-2-(5,6-Dimethoxy-1,2,3,4-tetrahydro-1-naphthyl)imidazoline has been resolved into its (+) and (-) enantiomers, and the absolute configuration was established by single-crystal X-ray diffraction studies. The more active isomer has been assigned the R absolute configuration. Cleavage of the respective (+)- and (-)-dimethyl ethers with boron tribromide provided the corresponding (+)- and (-)-2-(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthl)imidazoline hydrobromides and these were pharmacologically characterized. In various preparations, the R enantiomer has been shown to be an extremely potent alpha agonist with preferential activity at the alpha 2-adrenergic receptor.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Imidazoles/farmacología , Naftalenos/farmacología , Tetrahidronaftalenos/farmacología , Animales , Perros , Femenino , Técnicas In Vitro , Masculino , Conformación Molecular , Norepinefrina/farmacología , Conejos , Ratas , Ratas Endogámicas , Estereoisomerismo , Difracción de Rayos XRESUMEN
A previous report of the adrenergic selectivity of 2- and 6-fluoronorepinephrine prompted us to formulate a hypothesis that accounted for this selectivity on the basis of a conformational preference induced by electrostatic repulsion between the aromatic fluorine atom and the side-chain hydroxyl group. A series of nitrogen-substituted catechol (aminomethyl)benzocyclobutenes, indanes, tetralins, and benzocycloheptenes were prepared, and when their radioligand binding affinities were determined, it was found that the overall pattern of binding affinity results supported the electrostatic repulsion hypothesis. The radioligand binding assay also revealed several highly alpha 2 selective adrenergic agents among these compounds, with the binding selectivity maximizing for compounds having nitrogen substituted with a group no larger than methyl and having a five-membered carbocyclic ring (i.e., 16, 17, and 19).
Asunto(s)
Agonistas alfa-Adrenérgicos/síntesis química , Receptores Adrenérgicos alfa/metabolismo , Agonistas alfa-Adrenérgicos/metabolismo , Animales , Fenómenos Químicos , Química Física , Electricidad , Masculino , Conformación Molecular , Movimiento (Física) , Ensayo de Unión Radioligante , Ratas , Receptores Adrenérgicos alfa/clasificación , Relación Estructura-ActividadRESUMEN
This paper correlates the X-ray structures of two 4-(beta-1-naphthylvinyl)pyridine analogues (one cis and one trans) with chemical and biological activity data for this class of cholineacetylase inhibitors. Our results suggest that one of the two proposed mechanisms for inhibition by this class of compounds better describes their efficacy. Previous arguments about coplanarity of the aromatic rings and nucleophilicty across the vinyl linkage need to be modified. Quantum calculations are also included and substantiate previous suggestions about the charge distribution across the vinyl linkages. An alternate new mechanism of inhibition is proposed to encompass the published data and more recent results discussed in this paper.
Asunto(s)
Colina O-Acetiltransferasa/antagonistas & inhibidores , Naftilvinilpiridina/farmacología , Piridinas/farmacología , Fenómenos Químicos , Química , Cisteína , Modelos Moleculares , Naftilvinilpiridina/análogos & derivados , Teoría Cuántica , Relación Estructura-Actividad , Compuestos de Sulfhidrilo , Azufre , Difracción de Rayos XRESUMEN
ABBOTT-81988 (A-81988), 2-(N-propyl-N[(2'-[1H-tetrazol-5-yl]biphenyl- 4yl)methyl] amino) pyridine-3-carboxylic acid, a nonpeptide angiotensin II (AII) antagonist was studied in the conscious spontaneously hypertensive rate (SHR) (male, 18 to 21 weeks) for cardiovascular effects of oral administration. Oral A-81988 at 0.3 to 3 mg/kg produced a dose-related 10 to 29% decrease in mean arterial pressure (MAP) in SHR (control, 161 to 177 mm Hg; n = 19) for 12 to 24 h without changing heart rate. Oral A-81988 at 3 mg/kg daily maintained MAP in SHR at normotensive levels (97 to 120 mm Hg) during a 5-day protocol with no rebound hypertension at termination of treatment. There was an increase in plasma renin activity in nanograms AI/milliliter/hour in SHR treated with A-81988 (32 +/- 3, n = 6 v 5 +/- 2, n = 6 for vehicle) during its antihypertensive action. The oral potency of A-81988 was enhanced about 10-fold in furosemide-treated SHR. The pressor response to AII was inhibited selectively in SHR even after an 8-day treatment with A-81988 (approximately 3 mg/kg/day orally). Total peripheral resistance was lowered and cardiac output unchanged in SHR administered A-81988 (3 mg/kg/day orally for 2 days). A-81988 (3 mg/kg orally) did not cause orthostatic hypotension in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Angiotensina II/antagonistas & inhibidores , Antihipertensivos/farmacología , Hemodinámica/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Ácidos Nicotínicos/farmacología , Tetrazoles/farmacología , Administración Oral , Animales , Antihipertensivos/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Ácidos Nicotínicos/administración & dosificación , Ratas , Ratas Endogámicas SHR , Tetrazoles/administración & dosificaciónRESUMEN
Abbott-81988 (A-81988), 2-(N-n-Propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4- yl)methyl]amino)pyridine-3-carboxylic acid is a potent, competitive, non-peptidic antagonist of angiotensin AT1 receptors. A-81988 was labeled with tritium to high specific activity (16 Ci/mmol) and radioligand binding assays performed in rat liver membranes. [3H]A-81988 bound with high affinity (KD = 0.57 nM) and the KD determined from kinetics assays was similar. Non-specific binding (defined with 10(-6) M angiotensin-II) was very low (< 6% at the KD). The binding of [3H]A-81988 was competitive and exhibited appropriate pharmacological specificity for compounds acting at angiotensin AT1 receptors. These properties demonstrate that [3H]A-81988 will be a useful radioligand for studies of angiotensin AT1 receptors in various tissues.
Asunto(s)
Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina , Hígado/metabolismo , Ácidos Nicotínicos/farmacología , Tetrazoles/farmacología , Animales , Unión Competitiva , Células Cultivadas , Hígado/efectos de los fármacos , Masculino , Ácidos Nicotínicos/metabolismo , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Tetrazoles/metabolismoRESUMEN
Quantitative structure-activity relationships of 44 substituted aminotetralin analogues with regard to dopamine (DA) uptake inhibitory potency are examined in this study. Lipophilic substituents at R3 and hydrophilic substituents at R6 and/or R9 positions, as well as the overall lipophilicity of the molecule contribute toward increasing the inhibitory potency. Unlike with norepinephrine uptake inhibition, little effects are seen from the nitrogen substituent. Among the ring substituents examined, an hydroxy group at the R6 position increases the DA uptake inhibitory potency, whereas a methoxy group at the R7 position decreases it. A comparative quantitative structure-activity relationship study shows that a bromine at the R6 position and/or hydrogen at the R9 position make the compound a better norepinephrine uptake inhibitor than a DA uptake inhibitor, whereas hydrogen at the R6 and/or a substituent larger than a propyl group at the R2 position make the compound a more potent DA uptake inhibitor.
Asunto(s)
Antagonistas de Dopamina , Tetrahidronaftalenos/farmacología , Animales , Química Encefálica/efectos de los fármacos , Fenómenos Químicos , Química Física , Lípidos/química , Masculino , Norepinefrina/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tetrahidronaftalenos/químicaRESUMEN
Quantitative structure-activity relationships of 57 substituted aminotetralin analogues, an overview of their syntheses, and their pharmacological activity are described in this study. Lipophilic substituents at R3 as well as the overall lipophilicity of the molecule contribute toward increasing the inhibitory potency. An ethyl group is preferred, and a group larger than a propyl is not desirable as a nitrogen substituent. Among the ring substituents examined, an hydroxy group at the R6 position and either an unsubstituted R9 position or a methoxy substituent at the R9 position increase the inhibitory potency, whereas a methoxy group at the R7 position decreases inhibitory potency.
Asunto(s)
Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/metabolismo , Tetrahidronaftalenos/farmacología , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tetrahidronaftalenos/químicaRESUMEN
2-(4-Amino-3,5-dichlorobenzyl)imidazoline hydrochloride (A-57219), has alpha 1-agonist/alpha 2-antagonist activity and was more effective and long-acting than oxymetazoline on canine nasal mucosa, in-vitro and in-vivo. Upon intranasal administration to dogs, the compound was devoid of systemic effects up to a concentration 1000 times that needed for local decongestant effect (1.65 micrograms, atomized from a 1 microgram mL-1 solution) suggesting limited mucosal absorption. After nasal administration to rats for 15 days at a concentration 1000 times greater than that required for nasal decongestion, no mucosal tissue toxicity or systemic effects were seen.
Asunto(s)
Imidazoles/farmacología , Descongestionantes Nasales/farmacología , Oximetazolina/farmacología , Agonistas alfa-Adrenérgicos , Resistencia de las Vías Respiratorias/efectos de los fármacos , Animales , Perros , Femenino , Imidazoles/farmacocinética , Imidazoles/toxicidad , Técnicas In Vitro , Masculino , Músculo Liso Vascular/efectos de los fármacos , Descongestionantes Nasales/farmacocinética , Descongestionantes Nasales/toxicidad , Oximetazolina/farmacocinética , Oximetazolina/toxicidad , Fenoxibenzamina/farmacología , Conejos , Ratas , Ratas Endogámicas , Vena Safena/efectos de los fármacosRESUMEN
Vascular contractile effects of postsynaptic alpha 2-adrenergic receptor stimulation are believed to involve transmembrane calcium influx. Although the current knowledge of the alpha 2-receptor response coupling of vascular smooth muscle contractions is still limited, the fundamental mechanism(s) may involve the extracellular calcium utilization process. This is mediated via the alpha 2-receptor operated calcium channel, which can be pharmacologically distinguished from that mediated via the potential-dependent calcium channel. Therefore, vascular selective alpha 2-antagonists may produce vasorelaxation via a calcium inhibitory action that is different from that of the typical calcium channel blockers. The literature on the in vitro isolated vascular tissue models has been reviewed with emphasis on the methodology for study of alpha 2-antagonist-induced vascular relaxation via selective blockade of the alpha 2-receptor-operated calcium channel. The alpha 2-adrenergic receptors, like alpha 1-receptors on vascular smooth muscle, serve an important role in the control of the arterial, as well as the venous tone in experimental animals and humans in relationship to sympathetic and humoral adrenergic activation of the cardiovascular system. Of particular importance is the possibility that alterations in vascular control of alpha 2-adrenergic mechanisms may lead to increased intracellular free calcium concentrations, thereby causing elevated vascular resistance and high blood pressure. This view is consistent with the long held concept that disturbances of cellular calcium metabolism play a primary role in the pathogenesis of various forms of hypertension. Consequently, selective blockade of vascular alpha 2-adrenergic receptors would be a feasible approach for antihypertensive therapy. This type of antihypertensive agent would be expected to exhibit fewer side effects with efficacy, directed towards the etiology of hypertension.
Asunto(s)
Antagonistas Adrenérgicos alfa/farmacología , Calcio/fisiología , Hipertensión/tratamiento farmacológico , Músculo Liso Vascular/efectos de los fármacos , Receptores Adrenérgicos alfa/efectos de los fármacos , Antagonistas Adrenérgicos alfa/uso terapéutico , Animales , Humanos , Hipertensión/fisiopatologíaAsunto(s)
Angiotensina II/antagonistas & inhibidores , Pirimidinas/síntesis química , Administración Oral , Animales , Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacocinética , Imidazoles/administración & dosificación , Imidazoles/síntesis química , Imidazoles/farmacocinética , Losartán , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Ratas , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tetrazoles/administración & dosificación , Tetrazoles/síntesis química , Tetrazoles/farmacocinéticaRESUMEN
BACKGROUND: The measurement of hyperphosphorylated tau (p-tau) in CSF has been proposed as a biomarker candidate for the prediction of Alzheimer disease (AD) in patients with mild cognitive impairment (MCI). However, a standard quantitative criterion of p-tau has not been evaluated. OBJECTIVE: To assess in a multicenter study the predictive accuracy of an a priori defined criterion of tau phosphorylated at threonine 231 (p-tau(231)) for the prediction of conversion from MCI to AD during a short-term observation interval. METHODS: The study included 43 MCI converters, 45 stable MCI (average follow-up interval = 1.5 years), and 57 healthy controls (at baseline only). Subjects were recruited at four international expert sites in a retrospective study design. Cox regression models stratified according to center were used to predict conversion status. Bootstrapped 95% CIs of classification accuracy were computed. RESULTS: Levels of p-tau(231) were a significant predictor of conversion (B = 0.026, p = 0.001), independent of age, gender, Mini-Mental State Examination, and ApoE genotype. For an a priori-defined cutoff point (27.32 pg/mL), sensitivity ranged between 66.7 and 100% and specificity between 66.7 and 77.8% among centers. The bootstrapped mean percentage of correctly classified cases was 79.95% (95% CI = 79.9 to 80.00%). Post hoc defined cutoff values yielded a mean bootstrapped classification accuracy of 80.45% (95% CI = 80.24 to 80.76%). CONCLUSIONS: An a priori defined cutoff value of p-tau(231) yields relatively stable results across centers, suggesting a good feasibility of a standard criterion of p-tau(231) for the prediction of Alzheimer disease.
Asunto(s)
Trastornos del Conocimiento/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Trastornos del Conocimiento/diagnóstico , Estudios Transversales , Estudios de Factibilidad , Femenino , Humanos , Internacionalidad , Masculino , Persona de Mediana Edad , Fosforilación , Valor Predictivo de las Pruebas , Estudios RetrospectivosRESUMEN
Serotonin (5-HT) is a potent bioactive substance known to function through a number of different receptor types and subtypes. In our attempt to develop new agents that would interact selectively at certain 5-HT receptors, especially the 5-HT1A subtype, 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT) served as a template for the design of novel agents sharing aspects of the pharmacophore of 8-OH-DPAT and 5-HT. 5-HT contains no center of asymmetry, and 8-OH-DPAT shows only very modest stereospecificity for 5-HT1A receptors. To develop agents having enhanced potency and selectivity for the 5-HT1A site, several ring systems offering enhanced conformational rigidity which approximate the oxygen to nitrogen interatomic distances of 8-OH-DPAT and (to a lesser extent) 5-HT were synthesized. Exemplary ring systems include the 8-alkoxy-hexahydroindeno[1,2-c]pyrrole, 5-alkoxy-hexahydro-1H-indeno-[2,1-c]pyridine, and 9-alkoxy-hexahydro-1H-benz[e]isoindole systems. These conformationally restricted molecules demonstrated moderate stereospecificity in their interaction with the 5-HT1A binding site, which was enhanced in compounds with larger nitrogen substituents. Appropriate choice of such derivatives led to highly potent compounds selective for 5-HT1A sites compared with their activity at other 5-HT and/or adrenergic receptors. The pharmacological profile of compounds which appear to act as agonists at 5-HT1A receptors in the central nervous system to lower blood pressure in animal models of hypertension is presented.
Asunto(s)
Receptores de Serotonina/metabolismo , Animales , Bioensayo , Sistema Cardiovascular/fisiopatología , Perros , Diseño de Fármacos , Técnicas In Vitro , Estructura Molecular , Ensayo de Unión Radioligante , Ratas , Ratas Endogámicas SHR , Receptores de Serotonina/efectos de los fármacosRESUMEN
Subtypes of alpha adrenergic receptors were studied using selective adrenergic agonists. A-53693, A-54741, and related compounds were evaluated for their affinity for alpha receptor subtypes using radioligand binding techniques. Efficacy and potency were also evaluated using in vitro bioassays of alpha-1 receptors in rabbit aorta smooth muscle and alpha-2 receptors in the phenoxybenzamine-pretreated canine saphenous vein. Active and inactive compounds were then submitted for computer-assisted molecular modeling evaluation to ascertain the structural requirements for optimal potency and selectivity. Rigid catecholamines such as A-53693 display a high degree of selectivity for alpha-2 compared to alpha-1 receptors, probably because of the unique regions of space at the ligand binding site occupied by active compounds. Imidazolines such as A-54741 also interact with extremely high affinity and potency for alpha-2 receptors, and to a lesser extent at alpha-1 receptors. The spatial domains occupied by phenethylamines and imidazolines differ, each having unique regions of permissable space at alpha receptors. Compounds such as A-53693 and A-54741 are extremely useful probes of the molecular interactions of alpha agonistic compounds which will help in the design of even more selective drugs for alpha adrenergic receptors.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Imidazoles/farmacología , Indoles/farmacología , Naftalenos/farmacología , Receptores Adrenérgicos alfa/clasificación , Tetrahidronaftalenos/farmacología , Agonistas alfa-Adrenérgicos/metabolismo , Animales , Perros , Imidazoles/metabolismo , Indoles/metabolismo , Isoindoles , Modelos Moleculares , Unión Proteica , Conejos , Ratas , Receptores Adrenérgicos alfa/efectos de los fármacos , Receptores Adrenérgicos alfa/metabolismo , Relación Estructura-Actividad , Tetrahidronaftalenos/metabolismoRESUMEN
ABBOTT-54741 was identified as a full alpha-adrenergic agonist; its interaction with the alpha-adrenergic receptor was compared to that of norepinephrine. ABBOTT-54741 lacks affinity for beta-adrenergic receptors. In radioligand binding studies, the affinity of ABBOTT-54741 for alpha 1-adrenoceptors (as measured against 3H-prazosin binding) was KI = 401 nM, and that for norepinephrine was 388 nM. The affinity of ABBOTT-54741 for alpha 2-adrenoceptors (as measured against 3H-rauwolscine binding) was greater than that of norepinephrine (KIA = 7 nM; KI NE = 37 nM). In vitro, ABBOTT-54741 exhibits high potency in vascular preparations (ED50NE/ED50A in rabbit aorta = 12.9; in phenoxybenzamine-treated dog saphenous vein = 188.5). In rabbit pulmonary artery, it shows greater potency for the presynaptic than postsynaptic receptors, corroborating the observations of selectivity obtained in binding studies. The observations in vivo reflect that in isolated tissues. In different species (dog, rat) and via different routes of administration (i.v., p.o., i.c.v., and nasal), ABBOTT-54741 exhibits cardiovascular effects reflecting the stimulation of both alpha 1- and alpha 2-adrenoceptors consistently with much greater potency than norepinephrine or any other alpha agonist known to the authors.
Asunto(s)
Agonistas Adrenérgicos/farmacología , Imidazoles/farmacología , Naftalenos/farmacología , Tetrahidronaftalenos/farmacología , Agonistas Adrenérgicos/administración & dosificación , Animales , Aorta/efectos de los fármacos , Perros , Hemodinámica/efectos de los fármacos , Hipertensión/fisiopatología , Imidazoles/administración & dosificación , Técnicas In Vitro , Masculino , Arteria Pulmonar/efectos de los fármacos , Conejos , Ensayo de Unión Radioligante , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas , Vena Safena/efectos de los fármacos , Tetrahidronaftalenos/administración & dosificaciónRESUMEN
In order to examine species and tissue differences in alpha 1 adrenoceptors, binding experiments were performed using 3H-prazosin and membrane homogenates of central nervous and peripheral tissues of rabbit (cortex and spleen), and rat (cortex, spleen, and liver). Saturation studies indicated one binding site for 3H-prazosin, with apparent log molar dissociation constants (pKD) ranging from 9.43 to 10.20. The rank orders of affinities of three competing antagonists (prazosin much greater than idazoxan greater than rauwolscine) and five agonists (cirazoline greater than clonidine approximately equal to (-)-norepinephrine greater than (-)-phenylephrine greater than (+)-norepinephrine) were typical of alpha 1 receptors in all tissues. There were small but significant differences in the mean affinities of rauwolscine, idazoxan and cirazoline among the five tissues. No significant differences in pseudo-Hill coefficients were observed among tissues, although agonist binding curves were shallow (.7 to .85) and prazosin competition curves were significantly steeper (greater than .85). Guanine nucleotide did not affect the position or slope of the (-)-norepinephrine competition profile in rat cortex. These results demonstrate a qualitative similarity among central and peripheral alpha 1 receptors of the rat and rabbit, with small differences observed between central and peripheral sites in both species.