RESUMEN
Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.
Asunto(s)
Benzofuranos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes , Compuestos Bicíclicos con Puentes/síntesis química , Antagonistas de la Serotonina/síntesis química , Animales , Benzofuranos/farmacología , Compuestos Bicíclicos con Puentes/farmacología , Cobayas , Frecuencia Cardíaca/efectos de los fármacos , Técnicas In Vitro , Indoles/farmacología , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Ratas , Ratas Endogámicas , Antagonistas de la Serotonina/farmacología , Relación Estructura-Actividad , TropisetrónRESUMEN
5-Aroyl-6-substituted-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carbo xylic acids were synthesized and assayed for analgesic and antiinflammatory activity. Several of these compounds, notably the 5-(4-fluoro- and 4-chlorobenzoyl)-6-methyl derivatives 25 and 26 and the 5-(4-methyl-, 4-fluoro-, 4-chloro-, and 4-methoxybenzoyl)-6-chloro congeners 31-34 were of equal or greater potency than indomethacin as antiinflammatory and analgesic agents both in acute and chronic animal models.
Asunto(s)
Analgesia , Inflamación/tratamiento farmacológico , Pirroles/uso terapéutico , Animales , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/uso terapéutico , Fenómenos Químicos , Química , Espectroscopía de Resonancia Magnética , Ratones , Pirroles/síntesis química , Ratas , Relación Estructura-ActividadRESUMEN
cis-4-(4-Phenoxy)-1-[1-oxo-2(R)-[4-[(2-sulfobenzoyl)amino)-1H- imidazol-1-yl]octyl]-L-proline derivatives represent a novel class of potent nonpeptide angiotensin II (Ang II) receptor antagonists. These compounds evolved from directed structure-activity relationship (SAR) studies on a lead identified by random screening. Further SAR studies revealed that acidic modification of the 4-phenoxy ring system produced a series of triacid derivatives possessing oral activity in pithed rats. The most potent compound, cis-4-[4-(phosphonomethyl)phenoxy]-1-[1-oxo-2(R)-[4-[(2-sulfobenzoyl+ ++) amino]-1H-imidazol-1-yl]octyl]-L-proline (1e), inhibited the pressor response to exogenously administered Ang II for periods up to 8 h following oral dosing. The antihypertensive activity of 1e was evaluated in the Lasix-pretreated conscious spontaneously hypertensive rat (SHR) where it produced a dose-dependent fall in blood pressure following oral dosing lasting > 12 h. Antagonists such as 1e may serve as useful therapeutic agents for the treatment of hypertension as well as for studying the role of Ang II in various disease states.
Asunto(s)
Angiotensina II/antagonistas & inhibidores , Antagonistas de Receptores de Angiotensina , Antihipertensivos/síntesis química , Animales , Antihipertensivos/farmacología , Masculino , Conejos , Ratas , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The rationale for uprighting mesially inclined molars has been presented. A technique has been described that requires a simple armamentarium and minimally impedes oral hygiene.
Asunto(s)
Maloclusión/terapia , Diente Molar/patología , Técnicas de Movimiento Dental/métodos , Adulto , Pilares Dentales , Humanos , Aparatos OrtodóncicosRESUMEN
1. Centric relation in patients without clinical signs or symptoms of mandibular dysfunction is a small range of mandibular positions. 2. The average range of shift was 0.302 mm mediolaterally and 0.278 mm anteroposteriorly for all five subjects. 3. There is no significant difference between the ranges of mandibular positions recorded using chin-point guidance, chin-point guidance with ramus support, or bimanual manipulation. 4. This technique of comparing mandibular positions dictated by centric relation records is sufficiently sensitive to reveal minimum ranges of biologic variation.
Asunto(s)
Oclusión Dental Céntrica , Registro de la Relación Maxilomandibular , Mentón/anatomía & histología , Articuladores Dentales , Humanos , Mandíbula/anatomía & histología , Mandíbula/fisiología , Movimiento , Dimensión VerticalRESUMEN
The thin-layer chromatography of imipramine on silica gel plates was studied in fifteen solvent systems. The mobility of imipramine labeled with deuterium in the methyl groups of the dimethylaminopropyl side chain differs markedly from that of unlabeled imipramine. Partial or complete separations between unlabeled and deuterated imipramine were observed in all basic and neutral solvent systems investigated, but not in weakly acidic solvents. Isotopic fractionations of imipramine were also found on alumina thin-layer plates, but were not detected in cellulose chromatography. In all thin-layer isotopic separations, the unlabeled compound migrates more rapidly than the deuterated molecule. These results can be explained by a stronger basicity of deuterated imipramine relative to its unlabeled counterpart.