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1.
BMC Infect Dis ; 21(1): 1128, 2021 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-34724919

RESUMEN

BACKGROUND: Refugees in Malaysia, who are afflicted by poverty, conflict and poor health, are vulnerable to a range of zoonotic infections in the deprived environmental and social conditions under which they live. Exposure to infections such as leptospirosis, for which rodents are primary hosts, is of particular concern. METHODS: A wellness program was conducted to determine the presence of antibodies against Leptospira (seroprevalence) in 11 refugee community schools and centers in the Klang Valley, Malaysia. A total of 433 samples were assessed for IgG and IgM antibodies against Leptospira, using enzyme-linked immunosorbent assays (ELISA). RESULTS: Overall Leptospira seroprevalence was 24.7%, with 3.0% being seropositive for anti-Leptospira IgG and 21.7% for anti-Leptospira IgM. Factors significantly associated with overall Leptospira seroprevalence included: age, ethnicity, pet ownership, knowledge of disease and awareness of disease fatality. For IgM seroprevalence, significant risk factors included sex, ethnicity, eating habits with hands, pet ownership, the presence of rats, walking in bare feet and water recreation visits. CONCLUSIONS: These findings highlight the need for improvements in health and well-being among the refugee community through disease awareness programs and provision of healthy behavior programs, particularly in hygiene and sanitation through community engagement activities.


Asunto(s)
Leptospira , Leptospirosis , Refugiados , Animales , Anticuerpos Antibacterianos , Humanos , Leptospirosis/epidemiología , Prevalencia , Ratas , Factores de Riesgo , Estudios Seroepidemiológicos
2.
Top Curr Chem ; 299: 93-119, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21630516

RESUMEN

14-Hydroxy-7,8-dihydromorphinone (oxymorphone) and its derivatives (oxycodone, naloxone, naltrexone) have become among the most important clinical agents to have been produced from opium. 14-Aminocodeinone and its 7,8-dihydro and morphinone derivatives are of more recent origin thanks to the work of Professor Gordon Kirby and his collaborators. The 14-amino parent compounds have proved of limited interest but their 14-acylamino- and 14-alkylamino derivatives have been extensively studied. The 4'-substituted cinnamoylamino-17-cyclopropylmethyl-7,8-dihydronormorphinones, C-CAM and M-CAM are the best available selective MOR irreversible antagonists and the related dihydrocodeinone MC-CAM, 4'-chloro-cinnamoylamino-17-cyclopropylmethyl-7,8-dihydronorcodeinone, is a long-acting MOR partial agonist with extended MOR-pseudoirreversible antagonist activity that could be a candidate for pharmacotherapy of opiate abuse/dependence.


Asunto(s)
Morfinanos/síntesis química , Morfinanos/farmacología , Animales , Humanos , Relación Estructura-Actividad
3.
Ecotoxicol Environ Saf ; 72(4): 1220-7, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-18992941

RESUMEN

Climatic and man-made impacts induced dynamic molecular responses in the South African freshwater crab, Potamonautes warreni. Adult crabs exhibited MT-like protein, binding Cd (0.02micromolg(-1) wet mass+/-0.02), Cu (0.326micromolg(-1) wet mass+/-0.15), and Zn (0.534micromolg(-1) wet mass+/-0.20). The native protein binding Cd, Cu, and Zn showed a respective molecular mass (M) of 9.10kDa+/-1.74, 8.95kDa+/-1.66, and 9.32kDa+/-0.93. With exposure to 0.2mgCd(2+)l(-1) for up to 21 days in 50% of these crabs approximately 90% of Cd was bound to the MT-like protein component (8.54kDa+/-1.64), coinciding with a Zn-bound MT-like component (8.2kDa+/-1.54). Less than 10% were bound in the high M protein component, suggesting a protective function of the protein. In the remaining crabs metals were bound to protein (6.8kDa) with a predominant Cu-binding component.


Asunto(s)
Braquiuros/metabolismo , Cadmio/toxicidad , Metaloproteínas/metabolismo , Metales/metabolismo , Contaminantes Químicos del Agua/toxicidad , Animales , Biomarcadores , Cadmio/metabolismo , Cobre/metabolismo , Citosol/metabolismo , Sistema Digestivo/metabolismo , Femenino , Agua Dulce , Hígado/metabolismo , Masculino , Metaloproteínas/química , Unión Proteica , Zinc/metabolismo
4.
Am J Trop Med Hyg ; 101(6): 1265-1271, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31628737

RESUMEN

Leptospirosis is a zoonotic bacterial disease caused by pathogenic species of the genus Leptospira. Disease incidence is known to be attributed to environmental and social conditions which promote the spread of reservoir hosts, primarily rodents. A well-being program was conducted to determine the seroprevalence and risk factors associated with leptospirosis in urban poor communities occupying low-cost flat accommodation and squatter settlements in the vicinity of Wilayah Persekutuan, Kuala Lumpur. Blood samples from a total of 532 volunteers were screened for the detection of IgG and IgM antibodies against leptospirosis using ELISA. Demographic data were collected for each participant through a questionnaire survey before blood collection. The overall seroprevalence was low (12.6%, n = 67/532; 95% CI: 9.9-15.7%), with 8.1% (n = 43/532) being seropositive for anti-Leptospira IgG, indicating previous infection, and 4.9% (n = 26/532) for anti-Leptospira IgM, indicating current infection. Two significant factors such as host age (P ≤ 0.01) and knowledge of disease transmission (P = 0.017) significantly influenced the presence of anti-Leptospira IgM, whereas the detection of anti-IgG indicated the presence of clean drinking water sources (P = 0.043). Despite the low prevalence, the transmission of leptospirosis does occur among urban poor communities, suggesting the need for undertaking public awareness programs.


Asunto(s)
Anticuerpos Antibacterianos/sangre , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Leptospirosis/epidemiología , Leptospirosis/inmunología , Adolescente , Adulto , Factores de Edad , Niño , Programas de Detección Diagnóstica/estadística & datos numéricos , Femenino , Humanos , Leptospira , Leptospirosis/transmisión , Malasia/epidemiología , Masculino , Persona de Mediana Edad , Pobreza/estadística & datos numéricos , Prevalencia , Medición de Riesgo , Factores de Riesgo , Estudios Seroepidemiológicos , Población Urbana/estadística & datos numéricos , Adulto Joven
5.
J Med Chem ; 50(21): 5176-82, 2007 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-17887741

RESUMEN

A new series of ligands has been synthesized where the cinnamoyl group of the 14-cinnamoylamino morphinones has been introduced to the 7alpha-substituent of the 6,14-bridged oripavine series. In vitro the compounds were mostly low efficacy partial agonists or antagonists with some selectivity for the mu opioid receptor, with evidence of micro efficacy in vivo. The similarity in SAR between these 6,14-bridged oripavines and the 14-cinnamoylamino series suggests a similar mode of interaction with the micro opioid receptor.


Asunto(s)
Analgésicos/síntesis química , Cinamatos/síntesis química , Antagonistas de Narcóticos , Receptores Opioides/agonistas , Tebaína/análogos & derivados , Analgésicos/farmacología , Animales , Unión Competitiva , Células CHO , Cinamatos/farmacología , Cricetinae , Cricetulus , Humanos , Ligandos , Ratones , Conformación Molecular , Ensayo de Unión Radioligante , Receptores Opioides delta/agonistas , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inhibidores , Relación Estructura-Actividad , Tebaína/síntesis química , Tebaína/farmacología
6.
Rev Soc Bras Med Trop ; 50(2): 239-242, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28562762

RESUMEN

INTRODUCTION:: This study aimed to develop a duplex endpoint PCR assay for rapid detection and differentiation of Leptospira strains. METHODS:: Primers were designed to target the rrs (LG1/LG2) and ligB (LP1/LP2) genes to confirm the presence of the Leptospira genus and the pathogenic species, respectively. RESULTS:: The assay showed 100% specificity against 17 Leptospira strains with a limit of detection of 23.1pg/µl of leptospiral DNA and sensitivity of 103 leptospires/ml in both spiked urine and water. CONCLUSIONS:: Our duplex endpoint PCR assay is suitable for rapid early detection of Leptospira with high sensitivity and specificity.


Asunto(s)
Cartilla de ADN , ADN Bacteriano , Leptospira/clasificación , Reacción en Cadena de la Polimerasa/métodos , ADN Bacteriano/aislamiento & purificación , Leptospira/genética , Leptospira/aislamiento & purificación , Sensibilidad y Especificidad , Especificidad de la Especie
7.
Parasit Vectors ; 10(1): 238, 2017 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-28506241

RESUMEN

BACKGROUND: The number of migrants working in Malaysia has increased sharply since the 1970's and there is concern that infectious diseases endemic in other (e.g. neighbouring) countries may be inadvertently imported. Compulsory medical screening prior to entering the workforce does not include parasitic infections such as toxoplasmosis. Therefore, this study aimed to evaluate the seroprevalence of T. gondii infection among migrant workers in Peninsular Malaysia by means of serosurveys conducted on a voluntary basis among low-skilled and semi-skilled workers from five working sectors, namely, manufacturing, food service, agriculture and plantation, construction and domestic work. METHODS: A total of 484 migrant workers originating from rural locations in neighbouring countries, namely, Indonesia (n = 247, 51.0%), Nepal (n = 99, 20.5%), Bangladesh (n = 72, 14.9%), India (n = 52, 10.7%) and Myanmar (n = 14, 2.9%) were included in this study. RESULTS: The overall seroprevalence of T. gondii was 57.4% (n = 278; 95% CI: 52.7-61.8%) with 52.9% (n = 256; 95% CI: 48.4-57.2%) seropositive for anti-Toxoplasma IgG only, 0.8% (n = 4; 95% CI: 0.2-1.7%) seropositive for anti-Toxoplasma IgM only and 3.7% (n = 18; 95% CI: 2.1-5.4%) seropositive with both IgG and IgM antibodies. All positive samples with both IgG and IgM antibodies showed high avidity (> 40%), suggesting latent infection. Age (being older than 45 years), Nepalese nationality, manufacturing occupation, and being a newcomer in Malaysia (excepting domestic work) were positively and statistically significantly associated with seroprevalence (P < 0.05). CONCLUSIONS: The results of this study suggest that better promotion of knowledge about parasite transmission is required for both migrant workers and permanent residents in Malaysia. Efforts should be made to encourage improved personal hygiene before consumption of food and fluids, thorough cooking of meat and better disposal of feline excreta from domestic pets.


Asunto(s)
Anticuerpos Antiprotozoarios/sangre , Factores Socioeconómicos , Toxoplasma/inmunología , Toxoplasmosis/epidemiología , Toxoplasmosis/inmunología , Migrantes , Adulto , Agricultura , Asia , Demografía , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Malasia/epidemiología , Masculino , Persona de Mediana Edad , Ocupaciones , Factores de Riesgo , Estudios Seroepidemiológicos , Toxoplasma/aislamiento & purificación , Toxoplasmosis/parasitología , Toxoplasmosis/transmisión
8.
J Med Chem ; 49(20): 6104-10, 2006 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-17004724

RESUMEN

The 14-aminodihydromorphinone and codeinone series of opioid ligands have produced a number of ligands of substantial interest. To investigate the importance of the 14-substituent, a series of analogues in which the side chain length is varied and the amide and alkene functions are reduced have been prepared. Binding affinity, particularly at the mu-opioid receptor (MOR), was largely determined by the aromatic group of the side chain. In the [35S]GTPgammaS functional assay, the ligands having a three-carbon side chain were more potent antagonists than their longer chain counterparts, while shorter, two-carbon chain analogues were of higher MOR efficacy, an effect that was confirmed in vivo. Wash-resistant binding was observed within this series and appeared to be unrelated to side-chain length.


Asunto(s)
Aminas/síntesis química , Derivados de la Morfina/síntesis química , Antagonistas de Narcóticos , Receptores Opioides/agonistas , Aminas/química , Aminas/farmacología , Analgésicos/síntesis química , Analgésicos/química , Analgésicos/farmacología , Animales , Línea Celular , Cricetinae , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Ligandos , Ratones , Derivados de la Morfina/química , Derivados de la Morfina/farmacología , Dimensión del Dolor , Ensayo de Unión Radioligante , Receptores Opioides/metabolismo , Receptores Opioides delta/agonistas , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inhibidores , Receptores Opioides mu/metabolismo , Estereoisomerismo , Relación Estructura-Actividad
9.
J Med Chem ; 49(17): 5333-8, 2006 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-16913723

RESUMEN

In recent years there has been substantial interest in the 14-aminodihydromorphinone derivatives methoclocinnamox (MC-CAM) and clocinnamox (C-CAM). To investigate the importance of the cinnamoyl ring substituent, a series of analogues have been prepared with chloro, methyl, and nitro substituents in the 2' and 4' positions. Despite some discrepancies between the in vitro and in vivo data, a clear SAR could be observed where the 2'-chloro and 2'-methyl ligands consistently displayed higher efficacy than their 4'-substituted analogues. The new series also followed the well-established SAR that 17-methyl ligands have greater efficacy at the mu opioid receptor than their 17-cyclopropylmethyl counterparts.


Asunto(s)
Cinamatos/farmacología , Codeína/análogos & derivados , Codeína/farmacología , Derivados de la Morfina/farmacología , Receptores Opioides mu/efectos de los fármacos , Cinamatos/síntesis química , Cinamatos/química , Codeína/síntesis química , Diseño de Fármacos , Ligandos , Estructura Molecular , Derivados de la Morfina/síntesis química , Derivados de la Morfina/química , Estereoisomerismo , Relación Estructura-Actividad
10.
Asia Pac J Public Health ; 28(4): 290-302, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-27044535

RESUMEN

The history and epidemiology of human leptospirosis in Malaysia from 1925 to 2012 are described. Previous studies have demonstrated that leptospirosis is an endemic disease in Malaysia occurring in both urban and rural locations. The number of cases has risen dramatically since the Ministry of Health Malaysia highlighted leptospirosis as a notifiable disease in 2010, with reported cases increasing from 248 cases in 2004 to 3604 in 2012. The incidence of infection among the population suggests that occupation, sex, age, ethnic background, water recreational activities, and sporting events are risk factors. A robust surveillance system is now in place to monitor temporal and spatial changes in the incidence and prevalence of infection and to identify risk areas and disease behavior. Despite extensive studies over the past decade, there is a still a need to describe local serovars in host carriers and the human population, with the view to develop an effective vaccine against leptospirosis.


Asunto(s)
Leptospirosis/epidemiología , Humanos , Incidencia , Malasia/epidemiología , Factores de Riesgo
11.
PLoS Negl Trop Dis ; 10(11): e0005110, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27806046

RESUMEN

A cross-sectional study of intestinal parasitic infections amongst migrant workers in Malaysia was conducted. A total of 388 workers were recruited from five sectors including manufacturing, construction, plantation, domestic and food services. The majority were recruited from Indonesia (n = 167, 43.3%), followed by Nepal (n = 81, 20.9%), Bangladesh (n = 70, 18%), India (n = 47, 12.1%) and Myanmar (n = 23, 5.9.2%). A total of four nematode species (Ascaris lumbricoides, Trichuris trichiura, Enterobius vermicularis and hookworms), one cestode (Hymenolepis nana) and three protozoan species (Entamoeba histolytica/dispar, Giardia sp. and Cryptosporidium spp.) were identified. High prevalence of infections with A. lumbricoides (43.3%) was recorded followed by hookworms (13.1%), E. histolytica/dispar (11.6%), Giardia sp. (10.8%), T. trichura (9.5%), Cryptosporodium spp. (3.1%), H. nana (1.8%) and E. vermicularis (0.5%). Infections were significantly influenced by socio-demographic (nationality), and environmental characteristics (length of working years in the country, employment sector and educational level). Up to 84.0% of migrant workers from Nepal and 83.0% from India were infected with intestinal parasites, with the ascarid nematode A. lumbricoides occurring in 72.8% of the Nepalese and 68.1% of the Indian population. In addition, workers with an employment history of less than a year or newly arrived in Malaysia were most likely to show high levels of infection as prevalence of workers infected with A. lumbricoides was reduced from 58.2% to 35.4% following a year's residence. These findings suggest that improvement is warranted in public health and should include mandatory medical screening upon entry into the country.


Asunto(s)
Parasitosis Intestinales/parasitología , Parasitosis Intestinales/transmisión , Parásitos/aislamiento & purificación , Adulto , Animales , Bangladesh , Estudios Transversales , Ambiente , Femenino , Helmintos/clasificación , Helmintos/genética , Helmintos/aislamiento & purificación , Humanos , India , Indonesia , Parasitosis Intestinales/epidemiología , Malasia/epidemiología , Malasia/etnología , Masculino , Persona de Mediana Edad , Mianmar , Nematodos/clasificación , Nematodos/genética , Nematodos/aislamiento & purificación , Parásitos/clasificación , Parásitos/genética , Migrantes/estadística & datos numéricos , Adulto Joven
12.
Cell Rep ; 16(10): 2666-2685, 2016 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-27568567

RESUMEN

Human haploinsufficiency of the transcription factor Tcf4 leads to a rare autism spectrum disorder called Pitt-Hopkins syndrome (PTHS), which is associated with severe language impairment and development delay. Here, we demonstrate that Tcf4 haploinsufficient mice have deficits in social interaction, ultrasonic vocalization, prepulse inhibition, and spatial and associative learning and memory. Despite learning deficits, Tcf4(+/-) mice have enhanced long-term potentiation in the CA1 area of the hippocampus. In translationally oriented studies, we found that small-molecule HDAC inhibitors normalized hippocampal LTP and memory recall. A comprehensive set of next-generation sequencing experiments of hippocampal mRNA and methylated DNA isolated from Tcf4-deficient and WT mice before or shortly after experiential learning, with or without administration of vorinostat, identified "memory-associated" genes modulated by HDAC inhibition and dysregulated by Tcf4 haploinsufficiency. Finally, we observed that Hdac2 isoform-selective knockdown was sufficient to rescue memory deficits in Tcf4(+/-) mice.


Asunto(s)
Metilación de ADN/genética , Memoria , Plasticidad Neuronal/genética , Proteína 2 Similar al Factor de Transcripción 7/metabolismo , Animales , Trastorno Autístico/complicaciones , Trastorno Autístico/patología , Trastorno Autístico/fisiopatología , Islas de CpG/genética , Metilación de ADN/efectos de los fármacos , Modelos Animales de Enfermedad , Facies , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Hipocampo/metabolismo , Histona Desacetilasa 2/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Hiperventilación/complicaciones , Hiperventilación/genética , Hiperventilación/patología , Hiperventilación/fisiopatología , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Discapacidad Intelectual/fisiopatología , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Ratones , Actividad Motora/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Inhibición Prepulso/efectos de los fármacos , Proteína 2 Similar al Factor de Transcripción 7/genética , Transcripción Genética/efectos de los fármacos , Vorinostat
13.
J Med Chem ; 48(2): 635-8, 2005 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-15658877

RESUMEN

The well-established Nenitzescu reaction of imines of beta-dicarbonyl systems, as their enamine tautomers, with benzoquinone has been applied to a wide range of such imines to give 5-hydroxyindoles, some of which are of significant biological importance. This reaction has now been extended to the benzylimines of simple ketones, including those of the potent mu-opioid receptor antagonists naltrexone and naloxone. The products of the latter reactions, 1'-benzyl-5'-hydroxyindolomorphinans (7), are potent delta-opioid receptor (DOR) antagonists, confirming the enhancement of DOR antagonist potency and selectivity resulting from the introduction of the 1'-benzyl group.


Asunto(s)
Cetonas/síntesis química , Naltrexona/análogos & derivados , Naltrexona/síntesis química , Receptores Opioides delta/antagonistas & inhibidores , Animales , Células CHO , Cricetinae , Cricetulus , Humanos , Isomerismo , Cetonas/química , Cetonas/farmacología , Naltrexona/química , Naltrexona/farmacología , Ensayo de Unión Radioligante
14.
J Med Chem ; 48(5): 1676-9, 2005 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-15743210

RESUMEN

Indolic N-benzylation of naltrindole reportedly extends the duration of delta-opioid receptor (DOR) antagonism. Similar modification of the kappa-opioid receptor (KOR) antagonist norBNI (1a) and its 17,17'-diNMe analogue (1d), a low potency mu-opioid receptor (MOR) partial agonist, was found to affect predominantly their MOR activity. When administered systemically in mouse antinociceptive assays, N-benzyl-norBNI (1b) had only MOR agonist activity of relatively short duration whereas on central administration it had only a KOR-antagonist action of extremely long duration.


Asunto(s)
Analgésicos/síntesis química , Naltrexona/análogos & derivados , Naltrexona/síntesis química , Pirroles/química , Receptores Opioides kappa/antagonistas & inhibidores , Analgésicos/química , Analgésicos/farmacología , Animales , Línea Celular , Guanosina 5'-O-(3-Tiotrifosfato)/farmacología , Humanos , Ratones , Naltrexona/química , Naltrexona/farmacología , Ensayo de Unión Radioligante , Receptores Opioides delta/efectos de los fármacos , Receptores Opioides mu/agonistas , Relación Estructura-Actividad
15.
Eur J Pharmacol ; 509(2-3): 117-25, 2005 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-15733546

RESUMEN

In the search for opioid agonists with delayed antagonist actions as potential treatments for substance abuse, the bridged morphinan BU74 (17-cyclopropylmethyl-3-hydroxy-[5beta,7beta,3',5']-pyrrolidino-2'[S]-phenyl-7alpha-methyl-6,14-endoetheno morphinan) (3f) was synthesized. In isolated tissue and [35S]GTPgammaS opioid receptor functional assays BU74 was shown to be a potent long-lasting kappa opioid receptor agonist, delta opioid receptor partial agonist and mu opioid receptor antagonist. In antinociceptive tests in the mouse, BU74 showed high efficacy and potent kappa opioid receptor agonism. When its agonist action had waned BU74 became an antagonist of kappa and mu opioid receptor agonists in the tail flick assay and of delta, kappa and mu opioid receptor agonists in the acetic acid writhing assay. The slow onset, long-duration kappa opioid receptor agonist effects of BU74 suggests that it could be a lead compound for the discovery of a treatment for cocaine abuse.


Asunto(s)
Hidrocarburos Aromáticos con Puentes/farmacología , Morfinanos/farmacología , Receptores Opioides kappa/agonistas , Ácido Acético , Analgésicos/farmacología , Animales , Benzomorfanos/farmacología , Unión Competitiva/efectos de los fármacos , Hidrocarburos Aromáticos con Puentes/química , Línea Celular Tumoral , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Cobayas , Calor/efectos adversos , Íleon/efectos de los fármacos , Íleon/metabolismo , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos ICR , Morfinanos/química , Antagonistas de Narcóticos/farmacología , Dolor/inducido químicamente , Dolor/etiología , Dolor/prevención & control , Dimensión del Dolor , Ensayo de Unión Radioligante , Receptores Opioides delta/agonistas , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inhibidores , Receptores Opioides mu/metabolismo , Radioisótopos de Azufre , Conducto Deferente/efectos de los fármacos , Conducto Deferente/metabolismo
16.
Chem Biodivers ; 2(2): 215-20, 2005 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-17191974

RESUMEN

We recently showed that substitution of a 5beta-methyl group allows the isolation of 14-alkenyldihydrocodeinones from the action of hot formic acid on certain dihydrothevinols. It has now been shown that, in those dihydrothevinols which are converted to stable side chain olefins by such treatment, introduction of a 5beta-methyl group results in the formation of new doubly bridged morphinan derivatives in addition to the dihydrocodeinones or olefins. The new morphinans have low affinities for opioid receptors.


Asunto(s)
Hidrocarburos Aromáticos con Puentes/síntesis química , Formiatos/química , Morfinanos/síntesis química , Analgésicos Opioides/síntesis química , Analgésicos Opioides/farmacología , Animales , Hidrocarburos Aromáticos con Puentes/farmacología , Células CHO , Catálisis , Cricetinae , Humanos , Estructura Molecular , Morfinanos/farmacología , Unión Proteica , Receptores Opioides/química , Receptores Opioides/metabolismo
17.
J Med Chem ; 58(10): 4242-9, 2015 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-25898137

RESUMEN

Buprenorphine is a successful analgesic and treatment for opioid abuse, with both activities relying on its partial agonist activity at mu opioid receptors. However, there is substantial interest in its activities at the kappa opioid and nociceptin/orphanin FQ peptide receptors. This has led to an interest in developing compounds with a buprenorphine-like pharmacological profile but with lower efficacy at mu opioid receptors. The present article describes aryl ring analogues of buprenorphine in which the standard C20-methyl group has been moved to the C7ß position, resulting in ligands with the desired profile. In particular, moving the methyl group has resulted in far more robust kappa opioid antagonist activity than seen in the standard orvinol series. Of the compounds synthesized, a number, including 15a, have a profile of interest for the development of drug abuse relapse prevention therapies or antidepressants and others (e.g., 8c), as analgesics with a reduced side-effect profile.


Asunto(s)
Antagonistas de Narcóticos/química , Antagonistas de Narcóticos/farmacología , Receptores Opioides kappa/metabolismo , Receptores Opioides/agonistas , Buprenorfina/análogos & derivados , Técnicas de Química Sintética , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos/métodos , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Antagonistas de Narcóticos/síntesis química , Antagonistas de Narcóticos/metabolismo , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/química , Receptores Opioides mu/metabolismo , Relación Estructura-Actividad , Receptor de Nociceptina
18.
Curr Pharm Des ; 10(7): 717-32, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-15032698

RESUMEN

The thevinols and orvinols derived from thebaine via the thebaine-methylvinyl ketone adduct (thevinone) were thoroughly investigated in the 1960's and 1970's by the Reckitt group. From this work a number of important opioids emerged. Buprenorphine is a mu partial agonist, kappa/delta-antagonist that is now used primarily in the treatment of heroin abuse and dependence though it was initially launched as an analgesic for the treatment of moderate to severe pain. Etorphine and dihydroetorphine are very potent mu agonists that have found application in veterinary and human medicine respectively. Diprenorphine is primarily a mu antagonist though it also has some kappa-partial agonist effects. It has high affinity for all types of opioid receptors and as a "universal" opioid ligand has been much in demand as a pharmacological tool. It has also been converted into a [11C] version for use in Positron Emission Tomography (PET) studies of brain function related to the opioid receptor system. More recent medicinal chemistry investigations have been concerned with gaining a greater understanding of buprenorphine's unique opioid profile. This has involved the synthesis and evaluation of a number of series of buprenorphine analogues in which the C20 t-butyl group has been constrained in a ring system. These studies have suggested that the methyls in the t-butyl group inhibit the conformational changes in the kappa-receptor required for generation of an agonist response. Introduction of a 7alpha-cinnamoylaminomethyl group in place of the orvinol tertiary alcohol function leads to selective irreversible mu antagonism.


Asunto(s)
Narcóticos/farmacología , Tebaína/análogos & derivados , Tebaína/farmacología , Animales , Diseño de Fármacos , Humanos , Ligandos , Dimensión del Dolor/efectos de los fármacos , Relación Estructura-Actividad
19.
J Med Chem ; 47(21): 5069-75, 2004 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-15456250

RESUMEN

The trans-(3,4)-dimethyl-4-(3-hydroxyphenyl)piperidines are a unique class of opioid antagonists that have recently provided selective antagonists for mu-opioid receptors (MOR) and kappa-opioid receptors (KOR). Molecular modeling indicated a strong structural similarity between the parent of this series and 2-amino-1,1-dimethyl-7-hydroxytetralin. In binding and in vitro functional assays, the aminotetralin derivatives displayed some overlap in SAR with that previously reported for the phenylpiperidine series, providing evidence for a common binding mode for the two series at opioid receptors. Introduction of a methoxy group in the 3-position increased potency at MOR and KOR receptors, suggesting that this aminotetralin skeleton can be utilized as a new scaffold for the design of selective opioid receptor antagonists.


Asunto(s)
Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides mu/antagonistas & inhibidores , Tetrahidronaftalenos/síntesis química , Sitios de Unión , Modelos Moleculares , Antagonistas de Narcóticos/síntesis química , Antagonistas de Narcóticos/química , Piperidinas/química , Relación Estructura-Actividad , Tetrahidronaftalenos/química
20.
J Med Chem ; 46(14): 3174-7, 2003 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-12825957

RESUMEN

In investigation of the effects of 14-substitution in the indolomorphinan series of delta-selective opioid ligands, 5,14-bridged indolomorphinans (4) were prepared from the equivalent dihydrothebainone acid-catalyzed rearrangement products of the dihydrothevinols. Though the new ligands generally had low affinity for opioid receptors and no delta-selectivity, 4b had high kappa-affinity and substantial selectivity which was also seen in the precursor morphinanone (3b). This indicates that the methylbenzylidene-substituted bridge in these compounds is a dominant kappa-opioid receptor binding motif.


Asunto(s)
Hidrocarburos Aromáticos con Puentes/síntesis química , Indoles/síntesis química , Morfinanos/síntesis química , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/metabolismo , Animales , Hidrocarburos Aromáticos con Puentes/química , Hidrocarburos Aromáticos con Puentes/farmacología , Células CHO , Cricetinae , Indoles/química , Indoles/farmacología , Ligandos , Morfinanos/química , Morfinanos/farmacología , Receptores Opioides mu/metabolismo
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