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1.
J Labelled Comp Radiopharm ; 57(10): 600-5, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25196195

RESUMEN

Bristol-Myers Squibb and others are developing drugs that target novel mechanisms to combat Alzheimer's disease. γ-Secretase inhibitors are one class of potential therapies that have received considerable attention. (R)-2-(4-Chloro-N-(2-fluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)phenylsulfonamido)-5,5,5-trifluoropentanamide (Avagacestat) is a γ-secretase-inhibiting drug that has been investigated by Bristol-Myers Squibb in preclinical and clinical studies. An important step in the development process was the synthesis of a carbon-14-labeled analog for use in a human absorption, distribution, metabolism, and excretion study and a stable isotope labeled analog for use as a standard in bioanalytical assays to accurately quantify the concentration of the drug in biological samples. Carbon-14 labeled Avagacestat was synthesized in seven steps in a 33% overall yield from carbon-14 labeled potassium cyanide. A total of 5.95 mCi was prepared with a specific activity of 0.81 µCi/mg and a radiochemical purity of 99.9%. (13) C6 -Labeled Avagacestat was synthesized in three steps in a 15% overall yield from 4-chloro[(13) C6 ]aniline. A total of 585 mg was prepared with a ultraviolet purity of 99.9%.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Oxadiazoles/síntesis química , Radiofármacos/síntesis química , Sulfonamidas/síntesis química , Radioisótopos de Carbono/química
2.
Nat Neurosci ; 9(2): 205-11, 2006 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-16415864

RESUMEN

The transcription factor DeltaFosB is induced in the nucleus accumbens (NAc) and dorsal striatum by the repeated administration of drugs of abuse. Here, we investigated the role of DeltaFosB in the NAc in behavioral responses to opiates. We achieved overexpression of DeltaFosB by using a bitransgenic mouse line that inducibly expresses the protein in the NAc and dorsal striatum and by using viral-mediated gene transfer to specifically express the protein in the NAc. DeltaFosB overexpression in the NAc increased the sensitivity of the mice to the rewarding effects of morphine and led to exacerbated physical dependence, but also reduced their sensitivity to the analgesic effects of morphine and led to faster development of analgesic tolerance. The opioid peptide dynorphin seemed to be one target through which DeltaFosB produced this behavioral phenotype. Together, these experiments demonstrated that DeltaFosB in the NAc, partly through the repression of dynorphin expression, mediates several major features of opiate addiction.


Asunto(s)
Morfina/farmacología , Narcóticos/farmacología , Núcleo Accumbens/efectos de los fármacos , Trastornos Relacionados con Opioides/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Animales , Western Blotting , Dinorfinas/metabolismo , Inmunohistoquímica , Hibridación in Situ , Ratones , Ratones Transgénicos , Núcleo Accumbens/fisiología , Recompensa
3.
J Pharmacol Exp Ther ; 324(2): 664-73, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-17967938

RESUMEN

Chronic treatment with Delta(9)-tetrahydrocannabinol (THC) produces tolerance to cannabinoid-mediated behaviors and region-specific adaptation of brain cannabinoid receptors. However, the relationship between receptor adaptation and tolerance is not well understood, and the dose-response relationship of THC-induced cannabinoid receptor adaptation is unknown. This study assessed cannabinoid receptor function in the brain and cannabinoid-mediated behaviors after chronic treatment with different dosing regimens of THC. Mice were treated twice per day for 6.5 days with the following: vehicle, 10 mg/kg THC, or escalating doses of 10 to 20 to 30 or 10 to 30 to 60 mg/kg THC. Tolerance to cannabinoid-mediated locomotor inhibition, ring immobility, antinociception, and hypothermia was produced by both ramping THC-dose paradigms. Administration of 10 mg/kg THC produced less tolerance development, the magnitude of which depended upon the particular behavior. Decreases in cannabinoid-mediated G-protein activation, which varied with treatment dose and region, were observed in autoradiographic and membrane guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS)-binding assays in brains from THC-treated mice. Agonist-stimulated [(35)S]GTPgammaS binding was reduced in the hippocampus, cingulate cortex, periaqueductal gray, and cerebellum after all treatments. Decreased agonist-stimulated [(35)S]GTPgammaS binding in the caudate-putamen, nucleus accumbens, and preoptic area occurred only after administration of 10 to 30 to 60 mg/kg THC, and no change was found in the globus pallidus or entopeduncular nucleus after any treatment. Changes in the CB(1) receptor B(max) values also varied by region, with hippocampus and cerebellum showing reductions after all treatments and striatum/globus pallidus showing effects only at higher dosing regimens. These results reveal that tolerance and CB(1) receptor adaptation exhibit similar dose-dependent development, and they are consistent with previous studies demonstrating less cannabinoid receptor adaptation in striatal circuits.


Asunto(s)
Adaptación Biológica/efectos de los fármacos , Encéfalo/efectos de los fármacos , Dronabinol/farmacología , Tolerancia a Medicamentos , Receptores de Cannabinoides/metabolismo , Adaptación Biológica/fisiología , Animales , Encéfalo/metabolismo , Agonistas de Receptores de Cannabinoides , Relación Dosis-Respuesta a Droga , Tolerancia a Medicamentos/fisiología , Masculino , Ratones , Ratones Endogámicos ICR , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología
4.
Int J Med Inform ; 112: 1-5, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29500006

RESUMEN

OBJECTIVE: Machine learning in healthcare, and innovative healthcare technology in general, require complex interactions within multidisciplinary teams. Healthcare hackathons are being increasingly used as a model for cross-disciplinary collaboration and learning. The aim of this study is to explore high school student learning experiences during a healthcare hackathon. By optimizing their learning experiences, we hope to prepare a future workforce that can bridge technical and health fields and work seamlessly across disciplines. METHODS: A qualitative exploratory study utilizing focus group interviews was conducted. Eight high school students from the hackathon were invited to participate in this study through convenience sampling Participating students (n = 8) were allocated into three focus groups. Semi structured interviews were completed, and transcripts evaluated using inductive thematic analysis. FINDINGS: Through the structured analysis of focus group transcripts three major themes emerged from the data: (1) Collaboration, (2) Transferable knowledge and skills, and (3) Expectations about hackathons. These themes highlight strengths and potential barriers when bringing this multidisciplinary approach to high school students and the healthcare community. CONCLUSION: This study found that students were empowered by the interdisciplinary experience during a hackathon and felt that the knowledge and skills gained could be applied in real world settings. However, addressing student expectations of hackathons prior to the event is an area for improvement. These findings have implications for future hackathons and can spur further research into using the hackathon model as an educational experience for learners of all ages.


Asunto(s)
Servicios de Salud Comunitaria/organización & administración , Atención a la Salud/organización & administración , Personal de Salud/educación , Servicios de Salud/normas , Aprendizaje , Estudiantes , Grupos Focales , Humanos , Relaciones Interprofesionales
5.
Org Lett ; 7(7): 1339-42, 2005 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-15787501

RESUMEN

[reaction: see text] A one-pot procedure was developed to efficiently prepare hexahydroindolinones containing a tethered furan ring. Reaction of a furanyl azide with Bu3P delivered the iminophosphorane, which was allowed to react with 1-methyl-(2-oxocyclohexyl)acetic acid to give the desired hexahydroindolinone ring system. Further treatment with trifluoroacetic acid afforded the tetracyclic lactam skeleton found in the alkaloid (+/-)-selaginoidine.


Asunto(s)
Furanos/química , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Alcaloides Indólicos/síntesis química , Ciclización , Furanos/síntesis química , Alcaloides Indólicos/química , Estructura Molecular , Plantas Medicinales/química , Estereoisomerismo
6.
Org Lett ; 6(22): 4029-31, 2004 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-15496091

RESUMEN

[reaction: see text] The synthesis of several cis-2,3,6-trisubstituted piperidines has been developed employing the aza-Achmatowicz oxidation as the key reaction step. Its usage is illustrated by the facile synthesis of the piperidin-3-ol alkaloids (+/-)-deoxocassine and (+/-)-azimic acid.


Asunto(s)
Compuestos Aza/química , Piperidinas/síntesis química , Alcaloides/síntesis química , Hidroxilación , Modelos Químicos , Oxidación-Reducción
7.
Org Lett ; 5(26): 5067-70, 2003 Dec 25.
Artículo en Inglés | MEDLINE | ID: mdl-14682766

RESUMEN

An NBS-promoted intramolecular electrophilic aromatic substitution reaction of a hexahydroindolinone derivative was used to assemble the tetracyclic core of the erythrinane skeleton. The resulting cyclized product was transformed into (+/-)-erysotramidine in three additional steps. The cyclization reaction is also successful using variously substituted aryl and furanyl bicyclic lactams under acidic conditions. [reaction: see text]


Asunto(s)
Erythrina/química , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Ciclización , Indicadores y Reactivos , Lactamas/química
9.
Neuropharmacology ; 61(8): 1470-6, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21907220

RESUMEN

The stable transcription factor ΔFosB is induced in the nucleus accumbens (NAc) by chronic exposure to several drugs of abuse, and transgenic expression of ΔFosB in the striatum enhances the rewarding properties of morphine and cocaine. However, the mechanistic basis for these observations is incompletely understood. We used a bitransgenic mouse model with inducible expression of ΔFosB in dopamine D(1) receptor/dynorphin-containing striatal neurons to determine the effect of ΔFosB expression on opioid and cannabinoid receptor signaling in the NAc. Results showed that mu opioid-mediated G-protein activity and inhibition of adenylyl cyclase were enhanced in the NAc of mice that expressed ΔFosB. Similarly, kappa opioid inhibition of adenylyl cyclase was enhanced in the ΔFosB expressing mice. In contrast, cannabinoid receptor-mediated signaling did not differ between mice overexpressing ΔFosB and control mice. These findings suggest that opioid and cannabinoid receptor signaling are differentially modulated by expression of ΔFosB, and indicate that ΔFosB expression might produce some of its effects via enhanced mu and kappa opioid receptor signaling in the NAc.


Asunto(s)
Núcleo Accumbens/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Receptor Cannabinoide CB1/metabolismo , Transducción de Señal/fisiología , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Nucleótidos de Adenina/farmacología , Adenosina Trifosfato/farmacocinética , Adenilil Ciclasas/metabolismo , Analgésicos Opioides/farmacología , Animales , Benzoxazinas/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Relación Dosis-Respuesta a Droga , Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Guanosina 5'-O-(3-Tiotrifosfato)/farmacocinética , Masculino , Ratones , Ratones Transgénicos , Morfolinas/farmacología , Naftalenos/farmacología , Núcleo Accumbens/efectos de los fármacos , Fosfopiruvato Hidratasa/genética , Isótopos de Fósforo/farmacocinética , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/genética , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/genética , Transducción de Señal/genética , Isótopos de Azufre/farmacocinética
10.
J Med Chem ; 52(5): 1416-27, 2009 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-19199782

RESUMEN

Opioid receptor selective antagonists are important pharmacological probes in opioid receptor structural characterization and opioid agonist functional study. Thus far, a nonpeptidyl, highly selective and reversible mu opioid receptor (MOR) antagonist is unavailable. On the basis of our modeling studies, a series of novel naltrexamine derivatives have been designed and synthesized. Among them, two compounds were identified as leads based on the results of in vitro and in vivo assays. Both of them displayed high binding affinity for the MOR (K(i) = 0.37 and 0.55 nM). Compound 6 (NAP) showed over 700-fold selectivity for the MOR over the delta receptor (DOR) and more than 150-fold selectivity over the kappa receptor (KOR). Compound 9 (NAQ) showed over 200-fold selectivity for the MOR over the DOR and approximately 50-fold selectivity over the KOR. Thus these two novel ligands will serve as leads to further develop more potent and selective antagonists for the MOR.


Asunto(s)
Analgésicos/síntesis química , Morfinanos/síntesis química , Naltrexona/análogos & derivados , Naltrexona/síntesis química , Receptores Opioides mu/antagonistas & inhibidores , Secuencia de Aminoácidos , Analgésicos/farmacología , Analgésicos Opioides/antagonistas & inhibidores , Analgésicos Opioides/farmacología , Animales , Sitios de Unión , Unión Competitiva , Células CHO , Cricetinae , Cricetulus , Diseño de Fármacos , Ligandos , Modelos Moleculares , Datos de Secuencia Molecular , Morfinanos/farmacología , Morfina/antagonistas & inhibidores , Morfina/farmacología , Naltrexona/farmacología , Ensayo de Unión Radioligante , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides mu/agonistas , Alineación de Secuencia , Relación Estructura-Actividad
11.
J Org Chem ; 72(2): 538-49, 2007 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-17221972

RESUMEN

The synthesis of various substituted bicyclic lactams by an acid-induced Pictet-Spengler reaction of tetrahydroindolinones bearing tethered heteroaromatic rings is presented. The outcome of the cyclization depends on the position of the furan tether, tether length, nature of the tethered heteroaromatic ring, and the substituent group present on the 5-position of the tethered heteroaryl group. A one-pot procedure was developed to efficiently prepare tetrahydroindolinones containing tethered furan rings. In a typical example, the reaction of furanyl azide 26 with n-Bu3P delivered iminophosphorane 27, which was allowed to react with a 1-alkyl-(2-oxocyclohexyl)acetic acid to provide the desired furanyl-substituted tetrahydroindolinone system 29. Treatment of 29 with trifluoroacetic acid afforded the tetracyclic lactam skeleton 30 found in the alkaloid (+/-)-selaginoidine.


Asunto(s)
Ácidos/química , Alcaloides Indólicos/síntesis química , Indoles/síntesis química , Catálisis , Ciclización , Alcaloides Indólicos/química , Indoles/química , Estructura Molecular , Estereoisomerismo
12.
J Pharmacol Exp Ther ; 323(1): 346-55, 2007 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17646430

RESUMEN

This study was conducted to assess the utility of unbound brain EC50 (EC50,u) as a measure of in vivo potency for centrally active drugs. Seven mu-opioid agonists (alfentanil, fentanyl, loperamide, methadone, meperidine, morphine, and sufentanil) were selected as model central nervous system drugs because they elicit a readily measurable central effect (antinociception) and their clinical pharmacokinetics/pharmacodynamics are well understood. Mice received an equipotent subcutaneous dose of one of the model opioids. The time course of antinociception and the serum and brain concentrations were determined. A pharmacokinetic/pharmacodynamic model was used to estimate relevant parameters. In vitro measures of opioid binding affinity (Ki) and functional activity [EC50 for agonist stimulated guanosine 5'-O-(3-[35S]thio)triphosphate binding] and relevant clinical parameters were obtained to construct in vitro-to-preclinical and preclinical-to-clinical correlations. The strongest in vitro-to-in vivo correlation was observed between Ki and unbound brain EC50,u (r2 approximately 0.8). A strong correlation between mouse serum and human plasma EC50 was observed (r2 = 0.949); the correlation was improved when corrected for protein binding (r2 = 0.995). Clinical equipotent i.v. dose was only moderately related to Ki. However, estimates of ED50 and EC50 (total serum, unbound serum, total brain, and unbound brain) were significant predictors of clinical equipotent i.v. dose; the best correlation was observed for brain EC50,u (r2 = 0.982). For each opioid, brain equilibration half-life in mice was almost identical to the plasma effect-site equilibration half-life measured clinically. These results indicate that the mouse is a good model for opioid human brain disposition and clinical pharmacology and that superior in vitro-to-preclinical and preclinical-to-clinical correlations can be achieved with relevant unbound concentrations.


Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/biosíntesis , Transportadoras de Casetes de Unión a ATP/biosíntesis , Analgésicos Opioides , Encéfalo/efectos de los fármacos , Modelos Biológicos , Receptores Opioides mu/agonistas , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/farmacología , Analgésicos Opioides/uso terapéutico , Animales , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Masculino , Ratones , Dolor/tratamiento farmacológico , Valor Predictivo de las Pruebas , Unión Proteica , Ensayo de Unión Radioligante
13.
J Org Chem ; 71(22): 8591-601, 2006 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-17064038

RESUMEN

cis-2-Methyl-6-substituted piperidin-3-ol alkaloids of the Cassia and Prosopis species are readily prepared by a combination of an aza-Achmatowicz oxidative rearrangement and dihydropyridone reduction followed by a stereoselective allylsilane addition to a N-sulfonyliminium ion. The stereochemical outcome of the reduction reaction can be attributed to steric hindrance between the pseudoaxially oriented 2,6-substituents and the equatorially approaching hydride reagent which explains the exclusive formation of the cis-alcohol by axial approach of the hydride. The unsaturation present in the (E)-methyl-pent-3-enoate side chain was removed by catalytic reduction, and the remaining ester group was converted to the corresponding Weinreb's amide. This key intermediate was utilized for the synthesis of azimic acid, deoxocassine, cassine, and spicigerine. The facile preparation of (S)-N-tosylamidofuran 16 and its conversion to the chiral Achmatowicz oxidation product 18 provide a formal chiral synthesis of these alkaloids.


Asunto(s)
Alcaloides/síntesis química , Cassia/química , Prosopis/química , Alcaloides/química , Estructura Molecular , Oxidación-Reducción , Estereoisomerismo
14.
Mol Pharmacol ; 70(1): 41-50, 2006 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-16571654

RESUMEN

Sphingosine-1-phosphate (S1P) and cannabinoid receptors are G-protein-coupled receptors that mediate the effects of S1P and endocannabinoids, respectively. Cannabinoid receptors also mediate the effects of Delta9-tetrahydrocannabinol, the primary psychoactive ingredient in marijuana, whereas S1P receptors contribute to the immunosuppressant effects of 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol (FTY720). FTY720 is a sphingosine analog that can prevent renal graft rejections and suppress a variety of autoimmune disorders in animal models and clinical trials. We now report that both FTY720 and sphingosine interact with CB1 but not CB2 cannabinoid receptors. FTY720 and sphingosine inhibited the binding of the CB1-selective antagonist [3H]N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide ([3H]SR141716A) and the cannabinoid agonist [3H](-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol ([3H]CP55,940) in a concentration-dependent manner in both CB1-expressing cell lines and mouse cerebellum. However, these compounds did not significantly alter [3H]CP55,940 binding to CB2 receptors. In G-protein activation assays, FTY720 and sphingosine inhibited the maximal stimulation of guanosine 5'-O-(3-[35S]thio)triphosphate binding by the cannabinoid agonist R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate (WIN55,212-2) in a concentration-dependent manner, and this antagonist effect was not mimicked by S1P. FTY720 and sphingosine also inhibited activation of extracellular signal-regulated kinases 1 and 2 and Akt by WIN55,212-2 in intact Chinese hamster ovary (CHO) cells expressing CB1 receptors and attenuated WIN55,212-2-stimulated internalization of a fluorescence-tagged CB1 receptor in CHO cells. Moreover, both FTY720 and sphingosine produced rightward shifts in the concentration-effect curves of cannabinoid agonists for G-protein activation, indicating that they act as competitive CB1 antagonists. These results suggest that the CB1 receptor could be a novel target of FTY720 and that sphingosine could be an endogenous CB11 antagonist.


Asunto(s)
Glicoles de Propileno/farmacología , Receptor Cannabinoide CB1/metabolismo , Esfingosina/análogos & derivados , Esfingosina/farmacología , Animales , Benzoxazinas , Unión Competitiva/efectos de los fármacos , Células CHO , Línea Celular , Cricetinae , Cricetulus , Ciclohexanos/metabolismo , Ciclohexanos/farmacología , Ciclohexanoles , Endocitosis/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Clorhidrato de Fingolimod , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Inmunosupresores/metabolismo , Inmunosupresores/farmacología , Ratones , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Morfolinas/metabolismo , Morfolinas/farmacología , Naftalenos/metabolismo , Naftalenos/farmacología , Fenoles/metabolismo , Fenoles/farmacología , Piperidinas/metabolismo , Piperidinas/farmacología , Glicoles de Propileno/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirazoles/metabolismo , Pirazoles/farmacología , Ensayo de Unión Radioligante , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB2/agonistas , Receptor Cannabinoide CB2/antagonistas & inhibidores , Receptor Cannabinoide CB2/metabolismo , Rimonabant , Esfingosina/metabolismo
15.
Bioorg Med Chem Lett ; 15(18): 4110-3, 2005 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-16005223

RESUMEN

A new class of cannabimimetic indoles, with 3-phenylacetyl or substituted 3-phenylacetyl substituents, has been prepared and their affinities for the cannabinoid CB1 and CB2 receptors have been determined. In general those compounds with a 2-substituted phenylacetyl group have good affinity for both receptors. The 4-substituted analogs have little affinity for either receptor, while the 3-substituted compounds are intermediate in their affinities. Two of these compounds, 1-pentyl-3-(2-methylphenylacetyl)indole (JWH-251) and 1-pentyl-3-(3-methoxyphenylacetyl)indole (JWH-302), have 5-fold selectivity for the CB1 receptor with modest affinity for the CB2 receptor. GTPgammaS determinations indicate that both compounds are highly efficacious agonists at the CB1 receptor and partial agonists at the CB2 receptor.


Asunto(s)
Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Cannabinoides/química , Indoles/química , Indoles/farmacología , Pentanos/química , Acetilación , Materiales Biomiméticos/clasificación , Materiales Biomiméticos/metabolismo , Indoles/síntesis química , Indoles/clasificación , Estructura Molecular , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/agonistas , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-Actividad
16.
Bioorg Med Chem ; 13(1): 89-112, 2005 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-15582455

RESUMEN

In an effort to improve indole-based CB(2) cannabinoid receptor ligands and also to develop SAR for both the CB(1) and CB(2) receptors, 47 indole derivatives were prepared and their CB(1) and CB(2) receptor affinities were determined. The indole derivatives include 1-propyl- and 1-pentyl-3-(1-naphthoyl)indoles both with and without a 2-methyl substituent. Naphthoyl substituents include 4- and 7-alkyl groups as well as 2-, 4-, 6-, 7-methoxy and 4-ethoxy groups. The effects of these substituents on receptor affinities are discussed and structure-activity relationships are presented. In the course of this work three new highly selective CB(2) receptor agonists were identified, 1-propyl-3-(4-methyl-1-naphthoylindole (JWH-120), 1-propyl-2-methyl-3-(6-methoxy-1-naphthoylindole (JWH-151), and 1-pentyl-3-(2-methoxy-1-naphthoylindole (JWH-267). GTPgammaS assays indicated that JWH-151 is a full agonist at CB(2), while JWH-120 and JWH-267 are partial agonists. Molecular modeling and receptor docking studies were carried out on a set of 3-(4-propyl-1-naphthoyl)indoles, a set of 3-(6-methoxy-1-naphthoyl)indoles and the pair of N-pentyl-3-(2-methoxy-1-naphthoyl)indoles. Docking studies indicated that the CB(1) receptor affinities of these compounds were consistent with their aromatic stacking interactions in the aromatic microdomain of the CB(1) receptor.


Asunto(s)
Indoles/química , Indoles/farmacología , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB2/agonistas , Alquilación , Animales , Unión Competitiva , Células CHO , Cricetinae , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Indoles/metabolismo , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Modelos Moleculares , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-Actividad
17.
Mol Pharmacol ; 66(5): 1275-84, 2004 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-15286206

RESUMEN

Cannabinoid CB(1) receptors in the cerebellum mediate the inhibitory effects of Delta(9)-tetrahydrocannabinol (THC) on motor coordination. Intracellular effects of CB(1) receptors include inhibition of adenylyl cyclase via activation of G(i/o) proteins. There is evidence for the convergence of other neuronal receptors, such as adenosine A(1) and GABA(B), with the cannabinoid system on this signaling pathway to influence motor function. Previous studies have shown that brain CB(1) receptors are desensitized and down-regulated by long-term THC treatment, but few studies have examined the effects of long-term THC treatment on downstream effector activity in brain. Therefore, these studies examined the relationship between CB(1), adenosine A(1), and GABA(B) receptors in cerebella of mice undergoing prolonged treatment with vehicle or THC at the level of G protein activation and adenylyl cyclase inhibition. In control cerebella, CB(1) receptors produced less than additive inhibition of adenylyl cyclase with GABA(B) and A(1) receptors, indicating that these receptors are localized on overlapping populations of cells. Long-term THC treatment produced CB(1) receptor down-regulation and desensitization of both cannabinoid agonist-stimulated G protein activation and inhibition of forskolin-stimulated adenylyl cyclase. However, G protein activation by GABA(B) or A(1) receptors was unaffected. It is noteworthy that heterologous attenuation of GABA(B) and A(1) receptor-mediated inhibition of adenylyl cyclase was observed, even though absolute levels of basal and forskolin- or G(s)-stimulated activity were unchanged. These results indicate that long-term THC administration produces a disruption of inhibitory receptor control of cerebellar adenylyl cyclase and suggest a potential mechanism of cross-tolerance to the motor incoordinating effects of cannabinoid, GABA(B), and A(1) agonists.


Asunto(s)
Inhibidores de Adenilato Ciclasa , Cerebelo/efectos de los fármacos , Dronabinol/farmacología , Receptor de Adenosina A1/metabolismo , Receptor Cannabinoide CB1/metabolismo , Receptores de GABA-B/metabolismo , Animales , Cerebelo/enzimología , Dronabinol/administración & dosificación , Proteínas de Unión al GTP/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología
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