RESUMEN
SSAO/VAP-1 is not only involved in the metabolism of biogenic and xenobiotic primary amines and in the production of metabolites with cytotoxic effects or certain physiological actions, but also plays a role, for example, as an adhesion molecule, in leukocyte trafficking, in regulating glucose uptake and in adipocyte homeostasis. Interest in the enzyme has been stimulated by the findings that the activities of the SSAOs are altered (mostly increased) in various human disorders, including diabetes, congestive heart failure, liver cirrhosis, Alzheimer's disease and several inflammatory diseases, although the underlying causes are often unknown. On the basis of their insulin-mimicking effect, SSAO substrates are possibly capable of ameliorating metabolic changes in diabetes, while SSAO inhibitors (somewhat of a contradiction) are of potential benefit in preventing diabetes complications, atherosclerosis and oxidative stress contributing to several disorders or modulating inflammation, and hence may be of substantial therapeutic value. Great efforts have been made to develop novel compounds which may lead to future drugs useful in therapy, based on their effects on SSAO/VAP-1, and some of the results relating to novel substrates and inhibitors are surveyed in the present review.
Asunto(s)
Amina Oxidasa (conteniendo Cobre)/antagonistas & inhibidores , Amina Oxidasa (conteniendo Cobre)/química , Monoaminooxidasa/química , Semicarbacidas/química , Enfermedad de Alzheimer/tratamiento farmacológico , Amina Oxidasa (conteniendo Cobre)/metabolismo , Aminas/química , Animales , Sangre/metabolismo , Bovinos , Moléculas de Adhesión Celular/metabolismo , Diabetes Mellitus/tratamiento farmacológico , Humanos , Concentración 50 Inhibidora , Plasma/metabolismo , Ratas , Especificidad por SustratoRESUMEN
Recent methodologies applied to the drug discovery process, such as genomics and proteomics, have greatly implemented our basic understanding of drug action and are giving more input to medicinal chemists, in finding genuinely new targets and opportunities for the development of drugs with original mechanisms of action. In this paper, an example of the successful application of some new techniques to the target enzymes with the Thymidylate Synthase (TS) function is given. The improved knowledge of the complex mechanism of the biological pathways in which thymidylate synthase is involved represents a unique chance to find new mechanism-based inhibitors, aimed to treat not only cancerous diseases, but also infectious pathologies. Thymidylate synthase (TS or ThyA) has long been considered as one of the best-known drug targets in the anti-cancer area, after which old and new drugs, such as 5-fluoro uracil and the anti-folate ZD1694, have been introduced into chemotherapy to treat solid tumours. Only a few attempts have been made to find non-classical anti-folate inhibitors that are dissimilar to the folate co-factor, with the aim of finding unshared protein target domains on the enzyme structure, in order to specifically inhibit TS enzymes from pathogens. Only recently from omic studies, a new Thymidylate Synthase Complementing Protein (TSCP or ThyX) has been identified in a number of pathogens, showing a different structure with respect to human TS, thus opening new avenues to specific inhibitions. A depiction of the most recent progress in the study of Thymidylate Synthase enzymes is presented in the following sections.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Antagonistas del Ácido Fólico/farmacología , Timidilato Sintasa/metabolismo , Antineoplásicos/uso terapéutico , Diseño de Fármacos , Inhibidores Enzimáticos/uso terapéutico , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Antagonistas del Ácido Fólico/uso terapéutico , Humanos , Datos de Secuencia Molecular , ARN Mensajero/genética , ARN Mensajero/metabolismo , Alineación de Secuencia , Relación Estructura-Actividad , Timidilato Sintasa/antagonistas & inhibidores , Timidilato Sintasa/químicaRESUMEN
Semicarbazide-sensitive amine-oxidase (SSAO) is present in various human tissues and in plasma. Oxidative deamination of short-chain aliphatic amines is catalyzed by this enzyme to afford the corresponding aldehydes, ammonia and hydrogen peroxide. Methylamine and aminoacetone have been recognized to be physiological substrates for SSAO. There are several pathological states where increased serum SSAO activity have been found, such as diabetes mellitus, congestive heart failure, multiple types of cerebral infarction, uraemia, and hepatic cirrhosis. The role of SSAO in pathophysiology of diabetes has been most extensively investigated. The elevated formation of the potentially cytotoxic products of the enzyme may contribute to the endothelial injury of blood vessels, resulting in the early development of severe atherosclerosis; it may also contribute to the pathogenesis of diabetic angiopathy. It is now suggested that SSAO inhibitors may prevent the development of atherosclerosis and diabetic complications as well. Inhibitors can be conveniently subdivided into the main groups of hydrazine derivatives, arylalkylamines, propenyl- and propargylamines, oxazolidinones, and haloalkylamines. Of them, aryl(alkyl)hydrazines, and 3-halo-2-phenylallylamines are generally very strong SSAO inhibitors. Most of these inhibitors of SSAO have been originally developed for other purposes, or they are simple chemical reagents with highly reactive structural element(s); these compounds have not been able to fulfil all criteria of high potency, selectivity, and acceptable toxicity. New potent compounds with selectivity and low toxicity are needed, which may prove useful tools for understanding the roles and function of SSAO, or they may even be valuable substances for treatment of various diseases.
Asunto(s)
Amina Oxidasa (conteniendo Cobre) , Amina Oxidasa (conteniendo Cobre)/antagonistas & inhibidores , Amina Oxidasa (conteniendo Cobre)/sangre , Amina Oxidasa (conteniendo Cobre)/fisiología , Arteriosclerosis/tratamiento farmacológico , Arteriosclerosis/prevención & control , Vasos Sanguíneos/efectos de los fármacos , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/enzimología , Diabetes Mellitus/prevención & control , Inhibidores Enzimáticos/uso terapéutico , Humanos , Estructura MolecularRESUMEN
Unsubstituted phenylpyridazinones 1a and 2a and their tricyclic analogues indenopyridazinone 3a, benzocinnolinone 4a, and benzocycloheptapyridazinone 5a were submitted to conformational analysis with Allinger's MM2(85) program in order to better define the relationship between the cardiovascular properties of some derivatives and their preferred conformations. Structures 1-4, giving rise to highly active compounds, were found to exist in a conformation showing a near-planar arrangement of the phenyl and the pyridazinone ring. On the contrary, 5, whose derivatives were inactive, shows two significantly populated conformations both markedly deviated from planarity. 1H NMR analysis of the tricyclic systems 3-5 was in full agreement with the molecular mechanics calculations.
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Fármacos Cardiovasculares , Piridazinas/farmacología , Animales , Fenómenos Químicos , Química , Espectroscopía de Resonancia Magnética , Cómputos Matemáticos , Ratones , Conformación Molecular , RatasRESUMEN
A number of 7-amino and 7-acylamino substituted 4,4a-dihydro-5H-indeno[1,2-c]pyridazin-3-ones have been synthesized as rigid congeners of hypotensive 6-aryl-5-methyl-4,5-dihydro-3(2H)-pyridazinones and tested as antihypertensive, antithrombotic, antiulcer, and antiinflammatory agents. Unlike the previously described 7-cyano derivative, which displayed only antiinflammatory action, the new series exhibited significant antihypertensive and antithrombotic properties. In this respect, the 7-amino (2b) and the 7-acetylamino (2c) derivatives were found to be the most potent and long lasting in reducing the blood pressure in spontaneously hypertensive rats and in protecting mice from the induction of thrombosis. These compounds, as well as the 7-(2-chloropropionyl) derivative 2d, also exhibited antiinflammatory activity; in addition, 2c,d were highly effective in inhibiting indomethacin-induced ulcers in the rat.
Asunto(s)
Antihipertensivos/síntesis química , Agregación Plaquetaria/efectos de los fármacos , Piridazinas/síntesis química , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacología , Antiulcerosos/síntesis química , Antiulcerosos/farmacología , Antihipertensivos/farmacología , Fibrinolíticos/síntesis química , Fibrinolíticos/farmacología , Cobayas , Técnicas In Vitro , Masculino , Ratones , Piridazinas/farmacología , Ratas , Ratas Endogámicas , Relación Estructura-ActividadRESUMEN
A still unknown tricyclic heterocyclic system (5) was synthesized from 6-hydroxy-2-methylpyridazin-3-one and its structure identified as 2,8-dichloro-6-methylpyrrolo[1,2-b:3,4-d']dipyridazin-5(6H)- one by spectroscopic investigations. Selective condensation of 5 with 2-[4-(2-substituted-phenyl)piperazin-1-yl]ethylamine gave the 2-arylpiperazinylethylamino-8-chloro derivatives 6a-c, which were investigated in binding studies toward the three alpha1-adrenergic and 5-HT1A-serotonergic receptor subtypes. They displayed high potency on all the assays and some selectivity for alpha1a and alpha1d subtypes.
Asunto(s)
Antagonistas Adrenérgicos/síntesis química , Piridazinas/síntesis química , Pirroles/síntesis química , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Antagonistas Adrenérgicos/química , Antagonistas Adrenérgicos/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Células CHO , Cricetinae , Humanos , Técnicas In Vitro , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Piridazinas/química , Piridazinas/farmacología , Pirroles/química , Pirroles/farmacología , Ensayo de Unión Radioligante , Receptores Adrenérgicos alfa 1/biosíntesis , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina 5-HT1 , Relación Estructura-Actividad , Conducto Deferente/efectos de los fármacos , Conducto Deferente/fisiologíaRESUMEN
Alkyl-5,6-diphenylpyridazine derivatives combining several main features of ACAT inhibitors, such as a long alkyl side chain linked to a heterocycle and the o-diphenyl system, were synthesized and tested. Moreover, modeling studies on representative terms were performed. Some compounds displayed ACAT inhibition in the micromolar range, both on the enzyme isolated from rat liver microsomes and in cell-free homogenate of murine macrophages.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Piridazinas/síntesis química , Esterol O-Aciltransferasa/antagonistas & inhibidores , Animales , Sistema Libre de Células , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Técnicas In Vitro , Macrófagos/efectos de los fármacos , Macrófagos/enzimología , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Modelos Moleculares , Piridazinas/química , Piridazinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
Three new series of tricyclic pyridazinones have been synthesized and tested in vitro in order to assess (i) their ability to inhibit aldose reductase enzyme (ALR2) and (ii) their specificity toward the target enzyme with respect to other related oxidoreductases, such as aldehyde reductase, sorbitol dehydrogenase, and glutathione reductase. The inhibitory capability of the most effective compounds (IC50 values ranging from 6.44 to 12.6 microM) appears to be associated with a rather significant specificity for ALR2. Molecular mechanics and molecular dynamic calculations performed on the ALR2-inhibitor complex give indications of specific interaction sites responsible for the binding, thus providing information for the design of new inhibitors with improved affinity for the enzyme.
Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Modelos Moleculares , Piridazinas/química , Animales , Bovinos , Glutatión Reductasa/metabolismo , L-Iditol 2-Deshidrogenasa/metabolismo , Conformación Molecular , Conformación Proteica , Relación Estructura-ActividadRESUMEN
Several substituted benzo[h]cinnolinones 3 and 3H-benzo[6,7]cyclohepta[1,2-c]pyridazinones 4, which were designed as less rigid congeners of 5H-indeno[1,2-c]pyridazinones 2, were synthesized and tested as antihypertensive, inotropic, antithrombotic, antiinflammatory, and antiulcer agents. While the seven-membered ring derivatives displayed only antithrombotic properties, which were comparable to that of acetylsalicylic acid, most of the benzo[h]cinnolinones exhibited significant antihypertensive, inotropic, and antithrombotic properties. In this respect, the 8-amino (3b) and 8-acetylamino (3c) together with the 4,4a-dehydro analogue of 3c (11) were found to possess the most potent and long-lasting antihypertensive activity. In particular, the dextro isomer of 3c was more active than the racemic form, with lower tachycardiac effects. Unlike the lower homologues 2, none of the compounds showed significant antiinflammatory or antiulcer activity.
Asunto(s)
Antihipertensivos/síntesis química , Presión Sanguínea/efectos de los fármacos , Cicloheptanos/síntesis química , Fibrinolíticos/síntesis química , Contracción Miocárdica/efectos de los fármacos , Piridazinas/síntesis química , Animales , Función Atrial , Cicloheptanos/farmacología , Fibrinólisis , Cobayas , Atrios Cardíacos/efectos de los fármacos , Técnicas In Vitro , Masculino , Ratones , Estructura Molecular , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/farmacología , Piridazinas/farmacología , Ratas , Ratas Endogámicas SHR , Relación Estructura-ActividadRESUMEN
QSAR models have been used for designing a series of compounds characterized by a N-phenylpiperazinylalkylamino moiety linked to substituted pyridazinones, which have been synthesized. Measurements of the binding affinities of the new compounds toward the alpha(1a)-, alpha(1b)-, and alpha(1d)-AR cloned subtypes as well as the 5-HT(1A) receptor have been done validating, at least in part, the estimations of the theoretical models. This study provides insight into the structure activity relationships of the alpha(1)-ARs ligands and their alpha(1)-AR/5-HT(1A) selectivity.
Asunto(s)
Antagonistas Adrenérgicos alfa/síntesis química , Piperazinas/síntesis química , Piridazinas/síntesis química , Receptores Adrenérgicos alfa 1/metabolismo , Antagonistas Adrenérgicos alfa/química , Antagonistas Adrenérgicos alfa/metabolismo , Animales , Aorta/efectos de los fármacos , Aorta/fisiología , Células CHO , Cricetinae , Células HeLa , Humanos , Técnicas In Vitro , Ligandos , Modelos Moleculares , Contracción Muscular , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Piperazinas/química , Piperazinas/metabolismo , Piridazinas/química , Piridazinas/metabolismo , Relación Estructura-Actividad Cuantitativa , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina/metabolismo , Receptores de Serotonina 5-HT1RESUMEN
The isoxazolo-[3,4-d]-pyridazin-7-(6H)-one (2) and its corresponding open derivatives 5-acetyl-4-amino-(4-nitro)-6-substituted-3(2H)pyridazinones (3, 4) were used as simplified substrates for the synthesis of new aldose reductase inhibitors with respect to the previously reported 5, 6-dihydrobenzo[h]cinnolin-3(2H)one-2 acetic acids (1). Moreover, a few derivatives lacking the 5-acetyl group were prepared. Several compounds derived from 2 displayed inhibitory properties comparable to those of Sorbinil. In this class the presence at position 6 of a phenyl carrying an electron-withdrawing substituent proved to be beneficial, independently from its position on the ring (5g,j-l). Acetic acid derivatives were more effective than propionic and butyric analogues. On the contrary, all the monocyclic compounds (6-8) were either inactive or only weakly active. The 3-methyl-4-(p-chlorophenyl)isoxazolo-[3,4-d]-pyridazin-7-(6H )-one acetic acid (5g), which proved to be the most potent derivative, was also investigated in molecular modeling studies, to assess possible similarities in its interaction with the enzyme, with respect to the model 1.
Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Isoxazoles/síntesis química , Piridazinas/síntesis química , Aldehído Reductasa/química , Animales , Bovinos , Inhibidores Enzimáticos/química , Isoxazoles/química , Cristalino/enzimología , Modelos Moleculares , Piridazinas/química , Relación Estructura-ActividadRESUMEN
A series of 3,8-diazabicyclo[3.2.1]octanes substituted either at the 3 position (compounds 1) or at the 8 position (compounds 2) by a chlorinated heteroaryl ring were synthesized, as potential analogues of the potent natural analgesic epibatidine. When tested in the hot plate assay, the majority of the compounds showed significant effects, the most interesting being the 3-(6-chloro-3-pyridazinyl)-3,8-diazabicyclo[3.2.1]octane (1a). At a subcutaneous dose of 1 mg/kg, 1a induced a significant increase in the pain threshold, its action lasting for about 45 min. 1a also demonstrated good protection at a dose of 5 mg/kg in the mouse abdominal constriction test, while at 20 mg/kg it completely prevented the constrictions in the animals. Administration of naloxone (1 mg/kg i.p.) did not antagonize its antinociception while mecamylamine (2 mg/kg i.p.) did, thus suggesting the involvement of the nicotinic system in its action. Binding studies confirmed high affinity for the alpha 4 beta 2 nAChR subtype (Ki = 4.1 +/- 0.21 nM). nAChR functional activity studies on three different cell lines showed that 1a was devoid of any activity at the neuromuscular junction. Finally, due to the analogy in their pharmacological profile with that of epibatidine, compounds were compared from a structural and conformational point of view through theoretical calculations and high-field 1H NMR spectroscopy. Results indicate that all of them present one conformation similar to that of epibatidine.
Asunto(s)
Analgesia , Analgésicos no Narcóticos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Piridazinas/síntesis química , Piridinas/química , Músculos Abdominales/fisiología , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Corteza Cerebral/metabolismo , Humanos , Cinética , Espectroscopía de Resonancia Magnética , Masculino , Mecamilamina/farmacología , Ratones , Modelos Moleculares , Conformación Molecular , Contracción Muscular/efectos de los fármacos , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Umbral del Dolor/efectos de los fármacos , Piridazinas/química , Piridazinas/farmacología , Ratas , Receptores Colinérgicos/efectos de los fármacos , Receptores Colinérgicos/fisiologíaRESUMEN
A new set of phthalein derivatives stemming from the lead compound, phenolphthalein, were designed to specifically complement structural features of a bacterial form of thymidylate synthase (Lactobacillus casei, LcTS) versus the human TS (hTS) enzyme. The new compounds were screened for their activity and their specificity against TS enzymes from different species, namely, L. casei (LcTS), Pneumocystis carinii (PcTS), Cryptococcus neoformans (CnTS), and human thymidylate synthase (hTS). Apparent inhibition constants (Ki) for all the compounds against LcTS were determined, and inhibition factors (IF, ratio between the initial rates of the enzymatic reaction in the presence and absence of each inhibitor) against each of the four TS species were measured. A strong correlation was found between the two activity parameters, IF and Ki, and therefore the simpler IF was used as a screening factor in order to accelerate biological evaluation. Compounds 5b, 5c, 5ba, and 6bc showed substantial inhibition of LcTS while remaining largely inactive against hTS, illustrating for the first time remarkable species specificity among TSs. Due to sequence homology between the enzymes, several compounds also showed high activity and specificity for CnTS. In particular, 3-hydroxy-3-(3-chloro-4-hydroxyphenyl)-6-nitro-1H, 3H-naphtho[1,8-c,d]pyran-1-one (6bc) showed an IF < 0.04 for CnTS (Ki = 0.45 microM) while remaining inactive in the hTS assay at the maximum solubility concentration of the compound (200 microM). In cell culture assays most of the compounds were found to be noncytotoxic to human cell lines but were cytotoxic against several species of Gram-positive bacteria. These results are consistent with the enzymatic assays. Intriguingly, several compounds also had selective activity against Cr. neoformans in cell culture assay. In general, the most active and selective compounds against the Gram-positive bacteria were those designed and found in the enzyme assay to be specific for LcTS versus hTS. The original lead compound was least selective against most of the cell lines tested. To our knowledge these compounds are the first TS inhibitors selective for bacterial TS with respect to hTS.
Asunto(s)
Antiinfecciosos/síntesis química , Clorofenoles/síntesis química , Cromonas/síntesis química , Inhibidores Enzimáticos/síntesis química , Timidilato Sintasa/antagonistas & inhibidores , Antibacterianos , Antiinfecciosos/química , Antiinfecciosos/farmacología , Línea Celular , Clorofenoles/química , Clorofenoles/farmacología , Cromonas/química , Cromonas/farmacología , Cryptococcus neoformans/enzimología , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Bacterias Grampositivas/efectos de los fármacos , Humanos , Lacticaseibacillus casei/enzimología , Modelos Moleculares , Fenolftaleína/química , Pneumocystis/enzimología , Especificidad de la Especie , Relación Estructura-ActividadRESUMEN
Pramlintide is a human amylin analog, under development by Amylin (originally in collaboration with Johnson & Johnson), as an adjunct with insulin for the potential prevention of complications of type I diabetes, and as a single agent for type II diabetes [279804], [295121], [305454]. In December 2000, Amylin submitted a US NDA seeking approval to market pramlintide as an adjunctive therapy for type 1 and 2 diabetics using insulin [392527]; the application was accepted for review by the FDA in January 2001 [396938], and was scheduled for review by the Endocrinologic and Metabolic Drugs Advisory Committee on July 26 2001 [408924]. In May 2001, Amylin submitted an MAA for pramlintide to the EMEA [411323] and in October 2001, Amylin received an approvable letter from the FDA for both Type I and insulin-using Type II diabetes; however, at this time, discussions with the FDA were ongoing regarding additional clinical work that was required before the NDA would be approved [425570].
Asunto(s)
Amiloide/uso terapéutico , Hipoglucemiantes/uso terapéutico , Amiloide/síntesis química , Amiloide/farmacología , Animales , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/metabolismo , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Polipéptido Amiloide de los Islotes PancreáticosRESUMEN
Calyx Therapeutics is developing the insulin sensitizer, CLX-0901, as an antidiabetic agent. CLX-0901 is the synthetic analog of CLX-0900 which was originally isolated from a plant source. Phase I and toxicological studies indicate that the compound is safe and well tolerated [363764]. As of March 2001, phase II studies had commenced [402737]. Other antidiabetics being investigated by Calyx include CLX-0301, CLX-0921, CLX-0940, CLX-0100 and CLX-0101 [376032].
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , Estilbenos/farmacología , Animales , Ensayos Clínicos como Asunto , Contraindicaciones , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/toxicidad , Resistencia a la Insulina , Estilbenos/farmacocinética , Estilbenos/uso terapéutico , Estilbenos/toxicidad , Relación Estructura-ActividadRESUMEN
Opioid receptor like-1 (ORL-1) has recently been indicated as a potentially useful target for the treatment of a number of central disorders and several other diseases. This review deals with non peptidic ligands at the ORL-1 receptor, focusing on their structural and binding properties. Agonism or antagonism evidenced from functional experiments is also commented. For some compounds, possible therapeutic applications are considered.
Asunto(s)
Receptores Opioides/efectos de los fármacos , Secuencia de Aminoácidos , Animales , Humanos , Ligandos , Datos de Secuencia Molecular , Receptores Opioides/química , Receptor de NociceptinaRESUMEN
Inhibition of ACAT, the enzyme which catalyses the intracellular formation of cholesteryl esters, is a very attractive target for the treatment of hypercholesterolaemia and atherosclerosis. However, in the past years many ACAT inhibitors gave disappointing results in clinical trials showing very low efficacy. In addition, their development was affected by the adrenotoxicity observed in many compounds. The discovery of two isoforms of the enzyme, namely ACAT1 and ACAT2, with different substrate specificity and different potential function, offers a precious information for planning selective inhibitors with reduced secondary effects. Today some potent, bioavailable and non adrenotoxic ACAT inhibitors are under clinical evaluation. Amongst others, a very promising compound is Avasimibe, presently in phase III clinical trials as anti-hyperlipidemic and anti-atherosclerotic agent. Finally, ACAT inhibitors have recently been proposed for the treatment of Alzheimer's disease.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Hipolipemiantes/farmacología , Esterol O-Aciltransferasa/antagonistas & inhibidores , Enfermedad de Alzheimer/tratamiento farmacológico , Arteriosclerosis/tratamiento farmacológico , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Humanos , Hiperlipidemias/tratamiento farmacológico , Hipolipemiantes/química , Hipolipemiantes/uso terapéutico , Esterol O-Aciltransferasa/metabolismoRESUMEN
Two 3,8 diazabicyclo (3.2.1.) octane derivates, namely DBO 17 and DBO 11, were studied for the opioid-like activity. In the rat brain membrane preparation binding studies, DBO 17 and DBO 11 showed a high affinity and selectivity for the mu opioid receptor (Ki's: 5.1 and 25 nM, respectively). DBO 17 and DBO 11 inhibited the nociceptive response in the hot-plate test of mice with ED50 values of 0.16 mg/kg and 0.44 mg/kg, respectively. The antinociceptive action of both DBO 17 and DBO 11 was blocked by naloxone. Tolerance to the antinociceptive action of DBO 17 and DBO 11 was present after 13 and 7 days of repeated treatment, respectively. Both DBO 17 and DBO 11 were ineffective in morphine-tolerant mice and vice versa. Chronic treatments (three times daily for seven consecutive days) of DBO 17 and DBO 11 induced a naloxone-precipitated withdrawal syndrome in DBO 17 treated mice similar to that in morphine treated mice, whereas in DBO 11 treated mice abstinence signs were virtually absent. These results indicate an interesting pharmacological profile that suggests these compounds as possible new candidates for the clinical treatment of pain.
Asunto(s)
Analgesia , Analgésicos/farmacología , Compuestos Aza/farmacología , Encéfalo/efectos de los fármacos , Compuestos Bicíclicos con Puentes/farmacología , Dolor/tratamiento farmacológico , Receptores Opioides mu/efectos de los fármacos , Analgésicos/antagonistas & inhibidores , Analgésicos/metabolismo , Analgésicos/uso terapéutico , Analgésicos Opioides/farmacología , Animales , Compuestos Aza/antagonistas & inhibidores , Compuestos Aza/metabolismo , Compuestos Aza/uso terapéutico , Encéfalo/metabolismo , Compuestos Bicíclicos con Puentes/antagonistas & inhibidores , Compuestos Bicíclicos con Puentes/metabolismo , Compuestos Bicíclicos con Puentes/uso terapéutico , Tolerancia a Medicamentos , Masculino , Ratones , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Opioides mu/metabolismoRESUMEN
Anew sequence, which encoded a novel G protein-coupled receptor, was disclosed by two different groups, using the nucleic acid probes based on the delta opioid receptor, first cloned in 1992. The new receptor, which Meunier called opioid-receptor-like 1 (ORL-1), was shown to share high homology with the opioid receptors and therefore thought to be a potential target for new analgesics. In this respect, the present review reports on the literature referring to ORL-1, to its natural ligand (nociceptin or orphanin FQ) and to several synthetic analogues recently described, both as agonists or antagonists at the receptor.
Asunto(s)
Analgésicos Opioides/farmacología , Receptores Opioides/efectos de los fármacos , Secuencia de Aminoácidos , Animales , Humanos , Datos de Secuencia Molecular , Receptor de NociceptinaRESUMEN
Ambasilide, a representative of Class III antiarrhythmics, was reported to prolong the cardiac action potential duration in the dog, with little or no effect on Ca and Na currents. We synthesised a series of ambasilide analogues, having the 3,8-diazabicyclo-[3.2.1]-octane moiety instead of the 3,7-diazabicyclo-[3.3.1]-nonane present in ambasilide. The compounds were tested both in vitro extracellular electrophysiological assays and by the conventional microelectrode technique. Most of them lengthened the effective refractory period (ERP) with no change or slight increase on the impulse conduction time (ICT). Similarly some of the tested compounds lengthened the action potential duration (APD), a typical Class III feature, without exerting any significant effect on the maximal rate of depolarization, therefore apparently lacking Class I antiarrhythmic activity.