RESUMEN
OBJECTIVE: The objective of the study is to assess how well the emergency department (ED) personnel succeed in instructing the patient at discharge. METHODS: In November and December 2016 at Peijas Hospital ED, Finland, a structured questionnaire was conducted during a phone interview on patients the day after discharge. RESULTS: A total of 132 patients interviewed. Ninety percent had received discharge instructions from the ED staff, most of them (75%) about medication. Almost half of the patients (45%) were satisfied with the communication at discharge, those not satisfied (47%) felt that the staff did not know enough of their background to give discharge instructions. Of the patients, 20% thought that they did not have the opportunity to ask questions during the guidance session, and 41% thought that the session was too short and restricted. Some patients (20%) felt that the instructions were ambiguous, but 63% (83/132) felt they were able to follow them well or very well. CONCLUSION: The pace of care in the ED is fast and duration of the stay is short. The patients must be able to take responsibility of their self-care. Failure to follow medical discharge instructions could lead to non-compliance. Attention should be paid to enhancing the quality of discharge instructing and the instructions provided by the ED personnel, as recurring visits and inquiry calls add to the ED workload.
Asunto(s)
Enfermeras y Enfermeros/normas , Alta del Paciente/normas , Anciano , Análisis de Varianza , Distribución de Chi-Cuadrado , Servicio de Urgencia en Hospital/organización & administración , Servicio de Urgencia en Hospital/estadística & datos numéricos , Femenino , Finlandia , Humanos , Masculino , Persona de Mediana Edad , Enfermeras y Enfermeros/estadística & datos numéricos , Satisfacción del Paciente , Encuestas y CuestionariosRESUMEN
Benzopyranoxazine (+)-7 (PD 128907) is the most dopamine (DA) D3 receptor-selective agonist presently known. The only structural feature which distinguishes 7 from the analogous nonselective naphthoxazines is an oxygen atom in the 6-position. To extend this series of tricyclic DA agonists we used a classic bioisoster approach and synthesized thiopyran analogues of 7, which have a sulfur atom in the 6-position. We prepared trans-4-n-propyl-3,4,4a,10b-tetrahydro-2H,5H-[1]benzothiopyrano[4, 3-b]-1,4-oxazin-9-ol (9, trans-9-OH-PTBTO), its enantiomers ((+)-9 and (-)-9), the racemic cis-analogue (10), and the racemic trans-sulfoxide (11) and studied the potency and selectivity for DA receptors of these compounds. As with other rigid DA agonists, the highest affinity for DA receptors resided in one of the enantiomers, in this case the (-)-enantiomer of 9. On the basis of a single-crystal X-ray analysis of a key intermediate, the absolute configuration of (-)-9 was found to be 4aS,10bR, which is homochiral with (+)-(4aR,10bR)-7. In contrast to (+)-7 however, (-)-9 displayed no selectivity for any of the DA receptors. In addition, it has affinity for 5HT1A receptors. (+/-)-cis-4-n-Propyl-3,4,4a,10b-tetrahydro-2H,5H-[1]benzothiopyrano++ +[4,3-b]-1,4-oxazin-9-ol (10), which was expected to be inactive, displayed affinity and selectivity for the DA D3 receptor, whereas the sulfoxide 11 displayed some DA D3 selectivity, but with a lower affinity. Further pharmacological evaluation revealed that (-)-9 is a very potent full agonist at DA D2 receptors and a partial agonist at DA D3 receptors. The cis-analogue (+/-)-10 displayed the same profile, but with lower potency. These findings were confirmed in vivo: in reserpinized rats (-)-9 displayed short-acting activation of locomotor activity (DA D2 agonism) and also lower lip retraction and flat body posture, (5HT1A agonism). Compound (+/-)-10 had no effect on locomotor activity. In unilaterally 6-OH-DA lesioned rats, (-)-9 gave short-acting locomotor activation. Furthermore, in microdialysis studies in rat striatum, (-)-9 potently decreased DA release, confirming its activation of presynaptic DA D2 receptors.
Asunto(s)
Benzopiranos/síntesis química , Óxidos S-Cíclicos/síntesis química , Agonistas de Dopamina/síntesis química , Morfolinas/síntesis química , Oxazinas/síntesis química , Receptores de Dopamina D2/agonistas , Animales , Benzopiranos/química , Benzopiranos/farmacología , Unión Competitiva , Células CHO , Cuerpo Estriado/metabolismo , Cricetinae , Cristalografía por Rayos X , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacología , Dopamina/metabolismo , Agonistas de Dopamina/química , Agonistas de Dopamina/farmacología , Masculino , Microdiálisis , Morfolinas/química , Morfolinas/farmacología , Actividad Motora/efectos de los fármacos , Oxazinas/química , Oxazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3 , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina 5-HT1 , Agonistas de Receptores de Serotonina/síntesis química , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of new analogues of N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl] 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide (1; GR127935) as potent and selective 5-HT(1B/1D) antagonists were synthesized and evaluated pharmacologically. Their receptor binding profiles were comparable to that of 1. The 1,3,4-oxadiazole isomer 2 and the 4'-aminocarbonyl and 4'-amidinyl analogues (9 and 10) of 1 had higher affinities at the rat 5-HT(1B) receptor (IC(50) = 0.93, 1. 3, and 0.5 nM, respectively) and calf 5-HT(1D) receptor (IC(50) = 37, 10, and 3 nM, respectively) than did 1 (1.6 and 52 nM for rat 5-HT(1B) and calf 5-HT(1D) receptors, respectively). In the functional in vitro testing of 5-HT(1B/1D) antagonistic properties, 2, 9, 10, 11b (O-demethylated derivative of 2), 13a (O-methylsulfonyl analogue of 2), and 16 (which differs from 2 with a sulfonamide linker) showed more pronounced effects in the K(+)-induced 5-HT release in the cortex of guinea pig than did 1 and 3 (SB224289). Compounds 2, 9, and 10 were equally potent as 1 in rabbit saphenous vein model (pA(2) > 9). A biochemical study of 2 with in vivo microdialysis in the rat brain showed that it is capable of augmenting citalopram (a selective serotonin reuptake inhibitor, SSRI) induced 5-HT release in rat ventral hippocampus, while preventing the decrease in acetylcholine release elicited by citalopram administration. The molecular structure of 2 was determined by single-crystal X-ray analysis. The log P and log D values of these compounds were calculated. This study contributes to the SAR study of N-piperazinylphenyl biphenylcarboxamides as selective and potent 5-HT(1B/1D) antagonists.
Asunto(s)
Compuestos de Bifenilo/síntesis química , Piperazinas/síntesis química , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/síntesis química , Sulfonamidas/síntesis química , Acetilcolina/metabolismo , Animales , Compuestos de Bifenilo/química , Compuestos de Bifenilo/metabolismo , Compuestos de Bifenilo/farmacología , Bovinos , Cristalografía por Rayos X , Cobayas , Hipocampo/metabolismo , Técnicas In Vitro , Masculino , Microdiálisis , Estructura Molecular , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Piperazinas/química , Piperazinas/metabolismo , Piperazinas/farmacología , Conejos , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Receptor de Serotonina 5-HT1B , Receptor de Serotonina 5-HT1D , Receptores de Serotonina/metabolismo , Vena Safena/efectos de los fármacos , Vena Safena/fisiología , Serotonina/metabolismo , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/metabolismo , Sulfonamidas/farmacologíaRESUMEN
A series of 2- or 8-trifluoromethylsulfonyloxy (TfO) and 2- or 8-methylsulfonyloxy (MsO) 11-piperazinyldibenzodiazepines, -oxazepines, and -thiazepines were synthesized and evaluated in pharmacological models for their potential clozapine-like properties. In receptor binding assays, the 2-TfO analogues (18a, GMC2-83; 24, GMC3-06; and previously reported GMC1-169, 9a) of the dibenzazepines have profiles comparable to that of clozapine, acting on a variety of CNS receptors except they lack M1 receptor affinity. Introduction of 2-TfO to clozapine leads to compound 9e (GMC61-39) which has a similar binding profile as that of clozapine including having M1 receptor affinity. Interestingly, the MsO analogues, as well as the 8-TfO analogues, have no or weak dopaminergic and serotonergic affinities, but all 8-sulfonyloxy analogues do have M1 affinities. In behavioral studies performed to indicate the potential antipsychotic efficacy and the propensity to induce EPS, 2-TfO analogues blocked effectively the apomorphine-induced climbing in mice in a dose-dependent manner with ED50 values (mg/kg) of 2.1 sc for 9a, 1.3 po for 18a, 2.6 sc for 24, and 8.2 sc for 9e. On the other hand, they showed a clear dose separation with regard to their ED50 values (mg/kg) for indicating catalepsy in rats (>44 sc for 9a, 28 po for 18a, 30 sc for 24, and >50 sc for 9e, respectively), thus implicating a more favorable therapeutic ratio (K/A, ED50 climbing/ED50 catalepsy) in comparison with typical neuroleptics such as haloperidol and isoclozapine. Furthermore, compound 18a was also demonstrated to be an orally potent DA antagonist with an ED50 value of 0.7 mg/kg po in the ex vivo L-DOPA accumulation model. The present study contributes to the SAR of 11-piperazinyldibenzazepines, and the 2-TfO analogues of 11-piperazinyldibenzazepines are promising candidates as clozapine-like atypical antipsychotics with low propensity to induce EPS.
Asunto(s)
Antipsicóticos/síntesis química , Benzazepinas/síntesis química , Piperazinas/síntesis química , Animales , Antipsicóticos/química , Antipsicóticos/metabolismo , Antipsicóticos/farmacología , Benzazepinas/química , Benzazepinas/metabolismo , Benzazepinas/farmacología , Encéfalo/metabolismo , Células CHO , Catalepsia/inducido químicamente , Cricetinae , Antagonistas de Dopamina/síntesis química , Antagonistas de Dopamina/química , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/farmacología , Humanos , Técnicas In Vitro , Masculino , Ratones , Estructura Molecular , Piperazinas/química , Piperazinas/metabolismo , Piperazinas/farmacología , Ratas , Ratas Wistar , Receptor Muscarínico M1 , Receptores Adrenérgicos alfa/metabolismo , Receptores Dopaminérgicos/efectos de los fármacos , Receptores Dopaminérgicos/metabolismo , Receptores Histamínicos H1/metabolismo , Receptores Muscarínicos/metabolismo , Receptores de Serotonina/metabolismo , Relación Estructura-ActividadRESUMEN
A number of sulfonic acid ester derivatives of serotonin (5-hydroxytryptamine; 5-HT; 1) were prepared and their affinities are compared to that of the reference compound 5-[[(trifluoromethyl)sulfonyl]oxy]-tryptamine (8b). The structure-affinity relationship (SAFIR) is discussed in terms of in vitro binding for cloned human h5-HT1A, h5-HT1B and h5-HT1D receptors. All tryptamine derivatives exhibited the best affinities for h5-HT1D receptors but still, these were comparatively lower than that of compound 8b. 5-Tosylated tryptamine 11b (Ki = 6 nM) and the sulfamate derivatives 13b and 14b (Ki = 7 and 11 nM, respectively) were found to have the highest affinities for the h5-HT1D receptor. Other tryptamine derivatives displayed moderate binding for h5-HT1A and h5-HT1B receptors, along with Ki values ranging from 14-20 nM for the h5-HT1D sites. In addition, the syntheses of two alkylamino side chain restricted derivatives are described. 3-Amino-6-[[(trifluoromethyl)sulfonyl]oxy]-1,2,3,4-tetrahydrocarbazol e 21, as well as 4-[5-[[(trifluoromethyl)sulfonyl]oxy]-1H-indol-3-yl]piperidines 24 and 25, induced a shift in selectivity in favor of the h5-HT1B receptor. The relatively longer distance between the basic amine and a hydrogen-bond accepting oxygen in 21, 24 and 25 as compared to the non-restricted tryptamines, is likely responsible for this observation.
Asunto(s)
Receptores de Serotonina/metabolismo , Triptaminas/química , Triptaminas/farmacología , Animales , Células COS , Cristalografía por Rayos X , Células HeLa , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Unión Proteica , Receptor de Serotonina 5-HT1B , Receptor de Serotonina 5-HT1D , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Triptaminas/metabolismoRESUMEN
A series of 1-, 3-, and 4-substituted analogs to the potent 5-HT1A against 8-(dipropylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1-carbaldehyde (5) were prepared and tested in vitro at 5-HT1A, 5-HT1D alpha, 5-HT1D beta, D2, and D3 receptors and in vivo for agonist activity in the 5-HTP and DOPA accumulation assays in reserpine-pretreated rats. Some of the compounds were resolved. The substituents used in the 1-position were chosen from a principal component analysis (PCA) plot constructed from both tabulated variables and variables calculated by semiempirical methods (PM3) and molecular mechanics software (MMX). Among the analogs prepared, some, e.g., compound 21, were equipotent to compound 5 with respect to 5-HT1A effects. All compounds were more or less selective for the 5-HT1A receptor, but many of the compounds displayed higher affinities for 5-HT1D alpha than for 5-HT1D beta receptors.
Asunto(s)
Indoles/farmacología , Receptores Dopaminérgicos/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Animales , Unión Competitiva , Disponibilidad Biológica , Células CHO , Cricetinae , Indoles/metabolismo , Indoles/farmacocinética , Masculino , Ratas , Ratas Sprague-Dawley , Receptores Dopaminérgicos/clasificación , Receptores Dopaminérgicos/metabolismo , Receptores de Serotonina/clasificación , Receptores de Serotonina/metabolismo , Relación Estructura-ActividadRESUMEN
(R)-11-Hydroxyaporphine (2) and (R)-11-hydroxy-10-methylaporphine (3) were synthesized from natural morphine by using new, short, and efficient synthetic sequences. The dopaminergic and serotonergic effects of 2 and 3 were evaluated by use of in vitro and in vivo test systems. The results indicate that 3 is a potent, selective, and efficacious 5-HT1A receptor agonist. In contrast, 2 is a partial 5-HT1A receptor agonist of low potency which has affinity also for central D1 and D2A receptors. The differences in pharmacological profiles were rationalized by modeling of ligand-receptor interactions using homology-based receptor models of the 5-HT1A and D2A receptor binding site. The selective and pronounced serotonergic effects of 3 appear to be due to the C10-methyl group, which is accommodated by a lipophilic pocket in the 5-HT1A receptor. In contrast, the C10-methyl group of 3 is not accommodated by the binding site model of the D2A receptor.
Asunto(s)
Aporfinas , Receptores de Dopamina D2/agonistas , Agonistas de Receptores de Serotonina , Adenilil Ciclasas/metabolismo , Animales , Aporfinas/síntesis química , Aporfinas/farmacología , Colforsina/farmacología , Gráficos por Computador , Cristalografía por Rayos X , Activación Enzimática , Humanos , Masculino , Microdiálisis , Ratas , Ratas Sprague-Dawley , Agonistas de Receptores de Serotonina/síntesis química , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
The non-specific phospholipase C from Bacillus cereus preferentially hydrolyses phosphatidylcholine but is also active against phosphatidylserine, phosphatidylethanolamine and at a much lower level, sphingomyelin. A minimal substrate model containing all required structural and configurational elements of a high affinity substrate was docked into the active site. The enzyme-substrate attachment points were from molecular interaction energy calculations using the program GRID and from a previous phosphate inhibitor complex structure. Available conformational space for the substrate was sampled by distance geometry calculations using the program DGEOM. This investigation clearly identifies the attacking nucleophile, a catalytically favourable orientation of the phosphate group in its tetra-, as well as its penta-, coordinated state and a crucial stabilizing environment for the alkoxide intermediate. Based on this information a complete catalytic cycle is proposed.
Asunto(s)
Bacillus cereus/enzimología , Fosfolipasas de Tipo C/química , Fosfolipasas de Tipo C/metabolismo , Sitios de Unión , Catálisis , Cristalografía por Rayos X , Cómputos Matemáticos , Modelos Biológicos , Modelos Químicos , Conformación Molecular , Ácidos Fosfatidicos/metabolismo , Esfingomielinas/metabolismo , Especificidad por SustratoRESUMEN
The enantiomers of 6,7,8,9-tetrahydro-N,N-di-n-propyl-3H-benz[e]indol-8- amine (S-(-)-2b and R-(+)-2b) and their corresponding 1-formyl analogs (S-(-)-6 and R-(+)-6) were prepared and evaluated pharmacologically for serotonergic and dopaminergic activity. The introduction of a formyl group in the 1-position shifted the pharmacological profile of 2b from a mixed D2/5-HT1A agonists to a selective 5-HT1A agonist (6). The enantiomers of 6 were agonists with full intrinsic activity and had an affinity comparable to that of 8-hydroxy-2-(di-n-propylamino)tetrahydronaphthalene (8-OH-DPAT). In contrast to 8-OH-DPAT, the enantiomers of compound 6 were found to have good oral availability.
Asunto(s)
Indoles/síntesis química , Agonistas de Receptores de Serotonina/síntesis química , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Administración Oral , Animales , Conducta Animal/efectos de los fármacos , Disponibilidad Biológica , Indoles/farmacocinética , Indoles/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , Agonistas de Receptores de Serotonina/farmacocinética , Agonistas de Receptores de Serotonina/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Racemic 5-methoxy-2-methyl-2-dipropylaminotetralin (3) has been prepared by a short synthetic route, in which the N,N-dipropyliminium perchlorate of 5-methoxy-2-tetralone (4) is a key intermediate. Racemic 3 was resolved by crystallization of the corresponding diastereomeric di-p-toluoyltartrates. The enantiomeric excess (%ee) of the phenolic derivatives of (+)-(R)- and (-)-(S)-3 [(+)-(R)- and (-)-(S)-2] was determined by 1H NMR spectroscopic analysis of the corresponding diastereomeric (-)-(R)-1,1'-binaphthyl-2,2'-diylphosphoric acid salts utilizing 13C satellites. X-ray crystallography established the absolute configuration of (-)-(S)-2.HCl. The enantiomers of 2 were tested for hippocampal output of 5-hydroxytryptamine, 5-hydroxyindoleacetic acid, and dihydroxyphenylacetic acid in rats by use of in vivo microdialysis. The (-)-(S)-enantiomer appeared to affect 5-HT-turnover, whereas (+)-(R)-2 was inactive. Results obtained provide support for the previously reported hypothesis that the inactivity of (-)-(S)-2 at central DA receptors is caused by the steric bulk of the C(2)-methyl group. This makes it possible to define a "DA D2 receptor essential volume."
Asunto(s)
Ácido 3,4-Dihidroxifenilacético/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralin/análogos & derivados , Hipocampo/metabolismo , Ácido Hidroxiindolacético/metabolismo , Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralin/síntesis química , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Cristalización , Diálisis , Hipocampo/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Masculino , Conformación Molecular , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D2/efectos de los fármacos , Estereoisomerismo , Difracción de Rayos XRESUMEN
The enantiomers of cis-7-hydroxy-3-methyl-2-(dipropylamino)tetralin (3) have been synthesized and evaluated for activity at central dopamine (DA), 5-hydroxytryptamine, and norepinephrine (NE) receptors, by use of biochemical and behavioral tests in rats. In addition, the affinities of the compounds for striatal [3H]spiroperidol and [3H]N-propylnorapomorphine binding sites were determined. The absolute configuration of the enantiomers was determined by X-ray diffraction of (+)-3. The pharmacological effects of both enantiomers are complicated, but (2R,3S)-7-hydroxy-3-methyl-2-(dipropylamino)tetralin [(-)-3] produced biochemical effects in vivo similar to those elicited by classical DA D2-receptor antagonists.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/análogos & derivados , Antagonistas de Dopamina , Tetrahidronaftalenos , 5-Hidroxitriptófano/metabolismo , Animales , Apomorfina/análogos & derivados , Apomorfina/metabolismo , Unión Competitiva , Bovinos , Fenómenos Químicos , Química Física , Simulación por Computador , Cristalografía , Dihidroxifenilalanina/metabolismo , Técnicas In Vitro , Isomerismo , Masculino , Conformación Molecular , Estructura Molecular , Actividad Motora/efectos de los fármacos , Ratas , Reserpina/farmacología , Espiperona/metabolismo , Relación Estructura-Actividad , Difracción de Rayos XRESUMEN
The conformation and molecular packing of permethylated beta-D-galactosyl-N-octadecanoyl-D-spingosine (cerebroside) was determined by X-ray single crystal analysis at 185 K (R = 0.16). The lipid crystallizes in the orthorhombic space group P2(1)2(1)2(1) with the unit cell dimensions a = 8.03, b = 7.04 and c = 88.10 A. The four molecules in the unit cell pack in a bilayer arrangement with tilting (48 degrees) hydrocarbon chains. The direction of the chain tilt alternates in the two bilayer halves and in adjacent bilayers. In order to define the effect of hydrogen bonds on the molecular conformation the structural features of the permethylated cerebroside are compared with that of unsubstituted cerebroside (I. Pascher and S. Sundell (1977) Chem. Phys. Lipids 20, 179). It is shown that methylation of the hydrogen donor groups does not affect the conformation of the ceramide part. However, by abolishing the intramolecular hydrogen bond between the amide N--H group and the glycosidic oxygen the galactose ring changes its orientation from layer-parallel to layer-perpendicular. Calculations using molecular mechanics, MM2(87), show that in natural cerebroside the intramolecular hydrogen bond stabilizes the theta 1 = -syn-clinal conformation about the C(1)--C(2) sphingosine bond by 2-2.5 kcal/mol compared to other staggered conformations. The significance of the L shape of the native cerebroside, making both the carbohydrate and polar ceramide groups accessible as a binding epitope in recognition processes, is discussed.
Asunto(s)
Glicoesfingolípidos , Ceramidas , Cerebrósidos , Cristalografía/métodos , Galactosa , Enlace de Hidrógeno , Metilación , Modelos Químicos , Conformación Molecular , Estructura MolecularRESUMEN
The conformation of the glycerol group of a number of diacyl and monoacyl (lyso) phospholipids differing in the chemical nature of the head group was studied by 1H high-resolution NMR and X-ray crystallography. The NMR measurements were carried out with solutions or micellar dispersions of the lipids in deuteriated organic solvents or 2H2O. Both solutions, in which the lipid is present as monomers, and lipid micelles give rise to good high-resolution NMR spectra exhibiting spin coupling hyperfine interactions. From 1H spin coupling it is concluded that there are two stable conformations about the glycerol C(2)-C(3) bond of phospholipids. One of these (rotamer A) is characterized by torsion angles theta 3 = antiperiplanar, theta 4 = +synclinal, and the other (rotamer B) by theta 3 = +synclinal, theta 4 = -synclinal. In both rotamers A and B the ester oxygens on the glycerol carbon atoms C(2) and C(3) are synclinal, and hence both types of rotamers readily allow the parallel alignment of the two hydrocarbon chains. By comparison of NMR and single-crystal X-ray data it is obvious that both conformations are minimum free energy conformations. Rotamer A is the conformation prevailing in phospholipid single-crystal structures. The conformation of rotamer B is also found in phospholipid single-crystal structures though to a lesser extent, e.g., in 2,3-dilauroyl-DL-glycero-1-phospho-N,N-dimethylethanolamine and 2,3-dimyristoyl-D-glycero-phospho-DL-glycerol. NMR measurements indicate that in liquid crystals the diacylglycerol part of phospholipids fluctuates between the two stable staggered conformations of rotamers A and B.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Glicerol , Fosfolípidos , Lisofosfolípidos , Espectroscopía de Resonancia Magnética , Conformación Molecular , Estructura Molecular , Difracción de Rayos XRESUMEN
A number of stereochemically well defined C3-methylated derivatives of the potent 5-hydroxytryptamine (5-HT) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) have been synthesized, and their stereochemical characteristics have been studies by use of NMR spectroscopy, X-ray crystallography, and molecular mechanics calculations. The compounds were tested for activity at central 5-HT and dopamine (DA) receptors, by use of biochemical and behavioral tests in rats. In addition, the ability of the cis- and trans-8-hydroxy-3-methyl-2-(di-n-propylamino)tetralins (15 and 11) to displace [3H]-8-OH-DPAT from 5-HT1A binding sites was evaluated. The stereoselectivity of the interaction of 11 and 15 with 5-HT receptors was much greater than that of 8-OH-DPAT. Observed rank order of potencies in the 5-HT1A binding assay corresponds to that in the in vivo biochemical assay.
Asunto(s)
Encéfalo/efectos de los fármacos , Naftalenos/farmacología , Receptores Dopaminérgicos/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Tetrahidronaftalenos/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Espectroscopía de Resonancia Magnética , Masculino , Metilación , Conformación Molecular , Ratas , Ratas Endogámicas , Relación Estructura-Actividad , Tetrahidronaftalenos/síntesis química , Difracción de Rayos XRESUMEN
The conformational characteristics of two series of 5-hydroxytryptamine (5-HT) receptor agonists, monophenolic N,N-dialkylated 2-aminotetralins and trans-2-phenylcyclopropylamines, have been studied by a combination of experimental (NMR spectroscopy) and theoretical (molecular mechanics and MNDO calculations) methods. In addition, molecular electrostatic potentials have been calculated for selected conformations and the absolute configuration of the potent 5-HT-receptor agonist (+)-cis-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin has been determined, by X-ray crystallography of the synthetic precursor, to be 1S,2R. Results obtained are discussed in terms of conformational, steric, and electronic requirements for 5-HT-receptor activation. It is suggested that different conformations of the 5-HT-receptor agonists (1R,2S)-2-(2-hydroxyphenyl)-N,N-di-n-propylcyclopropylamine [(1R,2S)-4] and its 3-hydroxy isomer (1R,2S)-5 are able to activate 5-HT receptors. The strongly increased stereoselectivity of 2, 4, and 5 as compared to that of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 1) is rationalized on the basis of steric factors. Conformational factors appear to be responsible for the inability of the trans-C1-methyl-substituted derivative of 1 to activate 5-HT receptors.
Asunto(s)
Naftalenos/síntesis química , Antagonistas de la Serotonina/síntesis química , Tetrahidronaftalenos/síntesis química , 8-Hidroxi-2-(di-n-propilamino)tetralin , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Electroquímica , Espectroscopía de Resonancia Magnética , Conformación Molecular , Ratas , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Relación Estructura-Actividad , Tetrahidronaftalenos/farmacología , Difracción de Rayos XRESUMEN
C1- and C3-methyl-substituted derivatives of the potent dopamine (DA) receptor agonist 7-hydroxy-2-(di-n-propylamino)tetralin (7-OH-DPAT) have been synthesized, and their conformational preferences have been studied by use of NMR spectroscopy, X-ray crystallography, and molecular mechanics (MMP2) calculations. The compounds were tested for activity at central DA receptors, by use of biochemical and behavioral tests in rats. (1S,2R)-7-Hydroxy-1-methyl-2-(di-n-propylamino)tetralin [(+)-10] was demonstrated to be sevenfold less potent than (2R)-7-OH-DPAT as a DA receptor agonist. The other new compounds were of lower potency or inactive.
Asunto(s)
Naftalenos/farmacología , Receptores Dopaminérgicos/metabolismo , Tetrahidronaftalenos/farmacología , Animales , Apomorfina/metabolismo , Espectroscopía de Resonancia Magnética , Metilación , Modelos Moleculares , Actividad Motora/efectos de los fármacos , Ratas , Relación Estructura-Actividad , Difracción de Rayos XRESUMEN
cis-10-Hydroxy-4-n-propyl-1,2,3,4,4a,5,6,10b -octahydrobenzo[f]quinoline (4) is a centrally acting serotonin (5-HT) receptor agonist of moderate potency. Due to its semirigid character and the obvious similarity between (4aR,10bS)-4 and more potent, centrally acting 5-HT receptor agonist cis-(1S,2R)-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin (2), we carried out the preparation (via resolution of 6, a precursor of 4) and the pharmacological testing of the enantiomers of 4. We were able to show that the active enantiomers of 4 and 2 coincide in terms of stereochemistry, i.e., that it is the 4aR,10bS enantiomer of 4 that is the more active one. The absolute configuration was assigned on the basis of single-crystal X-ray analysis of the precursor (+)-6 of the active enantiomer (-)-4. Conformational analysis with molecular mechanics (MM2) calculations were performed on the N-methyl analogues of compounds cis-(1S,2R)-2 (cis-(1S,2R)-3) and cis-(4aR,10bS)-4 (cis-(4aR,10bS)-7). Both ammonium and free amine forms were subjected to these calculations. The results show a preference for the N-equatorial conformation, which is corroborated by the X-ray structure of (+)-6.HCl. The relatively low potency of compound cis-(4aR,10bS)-4 might be explained by unfavorable direction of the N-lone pair (or ammonium hydrogen) bond in this compound as compared to cis-(1S,2R)-2 and trans-(4aR,10bR)-5, which can be predicted to be the more active enantiomer of compound 5.
Asunto(s)
Hidroxiquinolinas/farmacología , Serotonina/metabolismo , Animales , Fenómenos Químicos , Química Física , Masculino , Modelos Moleculares , Ratas , Ratas Endogámicas , Receptores Dopaminérgicos/metabolismo , Receptores de Serotonina/metabolismo , Relación Estructura-Actividad , Difracción de Rayos XRESUMEN
C3-Methyl-substituted derivatives of the potent dopamine (DA) receptor agonist 5-hydroxy-2-(di-n-propylamino)tetralin (5-OH-DPAT) have been synthesized and their conformational preferences have been studied by use of NMR spectroscopy, X-ray crystallography, and molecular mechanics calculations (MMP2). The compounds were tested for activity at central DA receptors, by use of biochemical and behavioral tests in rats. (2R,3S)-5-Hydroxy-3-methyl-2-(di-n-propylamino)tetralin [(-)-8] was demonstrated to be a highly potent DA receptor agonist, while the other new compounds were of low potency or inactive. Results obtained confirmed the hypothesis that the tetralin inversion angle phi and the direction of the N-electron pair (N-H) tau N are conformational parameters of critical importance for DA D2 receptor activation in the 2-aminotetralin series. The high potency of (-)-8 allowed an extension of a previously defined "partial DA D2 receptor excluded volume".
Asunto(s)
Encéfalo/efectos de los fármacos , Naftalenos/síntesis química , Receptores Dopaminérgicos/efectos de los fármacos , Tetrahidronaftalenos/síntesis química , Animales , Masculino , Conformación Molecular , Actividad Motora/efectos de los fármacos , Ratas , Ratas Endogámicas , Relación Estructura-Actividad , Tetrahidronaftalenos/farmacologíaRESUMEN
Eight indolizidine and quinolizidine derivatives of 3-PPP were synthesized and tested for possible dopamine (DA) autoreceptor activity. The equatorial indolizidine derivative 19e had the profile of a selective autoreceptor agonist and was half as active as 3-PPP. However, resolution of the compound revealed that the 8R enantiomer was an unselective DA agonist with a profile similar to (+)-3-PPP, while the 8S enantiomer was a weak DA antagonist without any DA agonist activity. The unsaturated quinolizidine derivative 21 also had the profile of a DA antagonist while the axial quinolizidine derivative 18a had an amphetamine-like profile in 6-OHDA-lesioned rats. All other derivatives were inactive. The observed structure-activity relationships were in agreement with existing DA receptor models, although these models are not apparently detailed enough to explain why the 8S enantiomer of 19e is inactive as a DA agonist.