RESUMEN
BACKGROUND: Dexmedetomidine is an alpha-2 (α2 ) adrenoceptor and imidazoline 1 (I1 ) receptor agonist that provides sedation without loss of respiratory drive. AIMS: The aim of this study was to elucidate the involvement of α2 -adrenoceptor and I1 receptor in the cardiorespiratory changes induced by dexmedetomidine in spontaneously breathing newborn rats. METHODS: An abdominal catheter to administer drugs and three subcutaneous electrodes to record electrocardiographic data were inserted into 2- to 5-day-old Wistar rats under isoflurane anesthesia. In individual chambers, each rat was intraperitoneally administered dexmedetomidine (50 µg·kg-1 ) followed 5 min later by normal saline or 1, 5, or 10 mg·kg-1 atipamezole (selective α2 -adrenoceptor antagonist) or efaroxan (α2 -adrenoceptor/I1 receptor antagonist). Cardiorespiratory indices were recorded before and after drug administration. RESULTS: The administration of dexmedetomidine alone resulted in significant changes to most of the cardiorespiratory indices examined. The addition of 5 or 10 mg·kg-1 atipamezole or 1 mg·kg-1 efaroxan completely ameliorated the dexmedetomidine-associated reduction in heart rate (HR). The addition of 1 mg·kg-1 atipamezole or 1 or 5 mg·kg-1 efaroxan completely ameliorated the dexmedetomidine-associated reduction in respiratory frequency. Mean inspiratory flow (VT /TI ; VT is tidal volume and TI is inspiratory time), which is an index of respiratory drive, was not significantly affected by the administration of dexmedetomidine alone (P = 0.273) or dexmedetomidine + atipamezole (P = 0.605, 0.153, 0.138 for 1, 5, 10 mg·kg-1 atipamezole, respectively); however, it was significantly decreased after the administration of dexmedetomidine + efaroxan (P = 0.029, <0.001, <0.001 for 1, 5, 10 mg·kg-1 efaroxan, respectively). CONCLUSIONS: Our results suggest that in newborn rats undergoing dexmedetomidine sedation, the α2 -adrenoceptor, but not I1 receptor, is involved in the regulation of HR and respiratory frequency, and that activation of the I1 receptor plays a major role in the maintenance of respiratory drive.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Dexmedetomidina/farmacología , Impulso (Psicología) , Hipnóticos y Sedantes/farmacología , Receptores de Imidazolina/agonistas , Respiración/efectos de los fármacos , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Animales , Animales Recién Nacidos , Temperatura Corporal , Electrocardiografía/efectos de los fármacos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Pletismografía , Embarazo , Ratas , Ratas WistarRESUMEN
BACKGROUND: Dexmedetomidine, a selective α2-adrenoceptor agonist, is a new sedative agent. OBJECTIVE: To examine the dexmedetomidine-associated changes in cardiorespiratory indices in spontaneously breathing newborn rats. METHODS: An abdominal catheter to administer drugs and subcutaneous electrodes to record electrocardiographic data were inserted into 2- to 4-day-old rats under isoflurane anesthesia; the rats were then placed in individual chambers. After recovery from the anesthesia, the rats received intraperitoneal administrations of normal saline (NS, vehicle), dexmedetomidine (50 µg·kg(-1)), or dexmedetomidine (50 µg·kg(-1)) followed 5 min later with NS or the selective α2-adrenoceptor antagonist atipamezole (1 mg·kg(-1)) (n = 10 in each group). Cardiorespiratory indices were recorded for each animal throughout the experiment. RESULTS: Dexmedetomidine administration significantly decreased heart rate (HR) and minute ventilation (V'E) (P < 0.05) compared with control, whereas NS administration did not. The decrease in HR and V'E after dexmedetomidine administration was significantly less in rats that received atipamezole (P < 0.05) than in those that received NS after dexmedetomidine administration. The dexmedetomidine-associated V'E depression was attributed to a significant decrease in respiratory frequency (fR) but not tidal volume (VT ). The change in fR was reversed by atipamezole administration, which itself induced no significant changes in HR and fR. CONCLUSION: In spontaneously breathing immature rats, dexmedetomidine administration significantly reduced HR and V'E. Because atipamezole fully reversed decreases in fR and therefore V'E, dexmedetomidine-related respiratory suppression occurs predominantly through α2-adrenoceptor-related suppression of fR.
Asunto(s)
Dexmedetomidina/farmacología , Hemodinámica/efectos de los fármacos , Hipnóticos y Sedantes/farmacología , Mecánica Respiratoria/efectos de los fármacos , Antagonistas Adrenérgicos alfa/farmacología , Anestesia por Inhalación , Anestésicos por Inhalación , Animales , Animales Recién Nacidos , Electrocardiografía , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Imidazoles/farmacología , Isoflurano , Embarazo , Ratas , Ratas Wistar , Volumen de Ventilación Pulmonar/efectos de los fármacosRESUMEN
A series of milnacipran analogs were synthesized and studied as monoamine transporter inhibitors, and several potent compounds with moderate lipophilicity were identified from the 1S,2R-isomers. Thus, 15l exhibited IC(50) values of 1.7nM at NET and 25nM at SERT, which were, respectively, 20- and 13-fold more potent than 1S,2R-milnacipran 1-II.
Asunto(s)
Antidepresivos/síntesis química , Antidepresivos/farmacología , Ciclopropanos/síntesis química , Ciclopropanos/farmacología , Norepinefrina/antagonistas & inhibidores , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Antidepresivos/química , Técnicas Químicas Combinatorias , Ciclopropanos/química , Humanos , Concentración 50 Inhibidora , Milnaciprán , Estructura Molecular , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Derivatives of milnacipran were synthesized and studied as monoamine transporter inhibitors. Potent analogs were discovered at NET (9k) and at both NET and SERT (9s and 9u). A pharmacophore model was established based on the conformational analysis of milnacipran in aqueous solution using NMR techniques and was consistent with the SAR results.
Asunto(s)
Ciclopropanos/química , Ciclopropanos/farmacología , Proteínas de Transporte Vesicular de Monoaminas/antagonistas & inhibidores , Acetamidas/química , Acetamidas/farmacología , Alquilación , Amidas/química , Amidas/farmacología , Indoles/química , Indoles/farmacología , Milnaciprán , Modelos Moleculares , Conformación Molecular , Resonancia Magnética Nuclear Biomolecular , Estereoisomerismo , Relación Estructura-Actividad , Proteínas de Transporte Vesicular de Monoaminas/químicaRESUMEN
Compounds with various activities and selectivities were discovered through structure-activity relationship studies of bicifadine analogs as monoamine transporter inhibitors. The norepinephrine-selective 2-thienyl compound S-6j was efficacious in a rodent pain model.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Proteínas de Transporte de Neurotransmisores/química , Animales , Células CACO-2 , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Proteínas de Transporte de Membrana/química , Proteínas de Transporte de Membrana/farmacología , Modelos Químicos , Neurotransmisores/metabolismo , Proteínas de Transporte de Neurotransmisores/antagonistas & inhibidores , Norepinefrina/química , Dolor , Ratas , Relación Estructura-ActividadRESUMEN
A series of milnacipran analogs containing a heteroaromatic group were synthesized and studied as monoamine transporter inhibitors. Many compounds exhibited higher potency than milnacipran at NET and NET/SERT with no significant change in lipophilicity. For example, compound R-26f was about 10-fold more potent than milnacipran with IC(50) values of 8.7 and 26nM at NET and SERT, respectively.
Asunto(s)
Ciclopropanos/síntesis química , Ciclopropanos/farmacología , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Técnicas Químicas Combinatorias , Ciclopropanos/química , Humanos , Milnaciprán , Estructura Molecular , Norepinefrina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/química , Relación Estructura-ActividadRESUMEN
Melanin-concentrating hormone receptor antagonists containing thieno- and a benzopyridazinone cores were designed and tested as potential anorectic agents. These ligands showed high affinity for the receptor, potent functional activity in vitro, and good oral bioavailabilty in rats. The thiophene analogue exhibited low iv clearance, long half-life, and high brain penetration. In obese rats, the thienopyridazinone demonstrated a dose-dependent reduction in feeding and body weight with doses between 1 and 10 mg kg-1.
Asunto(s)
Depresores del Apetito/síntesis química , Piridazinas/síntesis química , Receptores de Somatostatina/antagonistas & inhibidores , Tiofenos/síntesis química , Animales , Depresores del Apetito/farmacocinética , Depresores del Apetito/farmacología , Disponibilidad Biológica , Peso Corporal/efectos de los fármacos , Encéfalo/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Semivida , Masculino , Obesidad/tratamiento farmacológico , Permeabilidad , Piridazinas/química , Piridazinas/farmacología , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Tiofenos/farmacocinética , Tiofenos/farmacologíaRESUMEN
Thien-2-yl 1S,2R-milnacipran analogues were synthesized and characterized as norepinephrine/serotonin transporter inhibitors. These compounds possessed higher potencies than 1S,2R-milnacipran (2R-1) while maintaining low molecular weight and moderate lipophilicity, which are the important features for the pharmacological and pharmacokinetic characteristics of milnacipran (1). Thus, compound 5c exhibited IC50 values of 2.3 and 32 nM, respectively, at NET and SERT, which were more than 10-fold better than those of 1 (NET IC50 = 77 nM, SERT IC50 = 420 nM). Moreover, 5c achieved the same efficacy as 1, but with much lower doses, in a rodent spinal nerve ligation pain model. In addition, 5c displayed desirable pharmacokinetic properties in several species, including high oral availability and significant brain penetration.
Asunto(s)
Ciclopropanos/farmacología , Neuralgia/tratamiento farmacológico , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Dimensión del Dolor/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Estereoisomerismo , Administración Oral , Animales , Disponibilidad Biológica , Células CACO-2 , Cristalografía por Rayos X , Ciclopropanos/química , Ciclopropanos/metabolismo , Ciclopropanos/farmacocinética , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Masculino , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Milnaciprán , Modelos Moleculares , Estructura Molecular , Peso Molecular , Neuralgia/patología , Ratas , Ratas Sprague-Dawley , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Nervios Espinales/patología , Nervios Espinales/cirugía , Relación Estructura-ActividadRESUMEN
A series of thienopyrimidinone bis-aminopyrrolidine ureas were designed, synthesized, and evaluated for their ability to bind melanin-concentrating hormone receptor-1. These compounds exhibit potent binding affinity (K(i)=3 nM) and good in vitro metabolic stability.
Asunto(s)
Química Farmacéutica/métodos , Pirrolidinas/química , Receptores de Somatostatina/antagonistas & inhibidores , Urea/análogos & derivados , Urea/química , Animales , Inhibidores del Citocromo P-450 CYP2D6 , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Cinética , Ratones , Modelos Químicos , Conformación Molecular , Unión Proteica , Relación Estructura-ActividadRESUMEN
The design, synthesis, and SAR of a series of substituted spirohydantoins are described. Optimization of an in-house screening hit gave compounds that exhibited potent binding affinity and functional activity at MCH-R1.
Asunto(s)
Fármacos Antiobesidad/síntesis química , Hidantoínas/síntesis química , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Compuestos de Espiro/síntesis química , Fármacos Antiobesidad/farmacología , Diseño de Fármacos , Humanos , Hidantoínas/farmacología , Cinética , Unión Proteica , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
A series of substituted chromones were designed, synthesized, and evaluated for their ability to bind melanin-concentrating hormone receptor 1. Compounds with subnanomolar binding affinity and 66% oral bioavailability in rats were discovered.
Asunto(s)
Química Farmacéutica/métodos , Cromonas/síntesis química , Melaninas/química , Quinolonas/síntesis química , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Receptores de la Hormona Hipofisaria/química , Administración Oral , Animales , Cromonas/química , Diseño de Fármacos , Humanos , Microsomas Hepáticos/metabolismo , Modelos Químicos , Quinolonas/química , Ratas , Factores de TiempoRESUMEN
The design, synthesis, and SAR of a series of retro bis-aminopyrrolidine ureas are described. Compounds from this series exhibited potent binding affinity and functional activity at MCH-R1, and good oral bioavailability in rat.
Asunto(s)
Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Urea/análogos & derivados , Animales , Estructura Molecular , Pirrolidinas/química , Ratas , Receptores de la Hormona Hipofisaria/metabolismo , Relación Estructura-Actividad , Urea/síntesis química , Urea/química , Urea/farmacologíaRESUMEN
Ureas derived from two substituted 3-aminopyrrolidine subunits were prepared as constrained analogs of a linear lead compound and tested as antagonists of the MCH(1) receptor. The series was optimized for substitution and stereochemistry to generate a functional antagonist with a K(i) of 3.3 nM and IC(50) of 12 nM (GTPgammaS).
Asunto(s)
Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Urea/química , Urea/farmacología , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Pirrolidinas/química , Pirrolidinas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel series of bis-aminopyrrolidine ureas containing either a 4-biphenylcarboxmide or 5-phenyl-2-thiophenecarboxamide group have been identified as potent and functional antagonists of the melanin-concentrating hormone receptor-1. Syntheses and SAR are described, which led to the discovery of compounds with high binding affinity (Ki = 1 nM) for the receptor. Preliminary in vitro metabolic stability data are also reported for key compounds.