RESUMEN
In Parkinson's disease (PD), dyskinesia develops following long-term treatment with 3,4-dihydroxyphenylalanine (L-dopa). Given the prominent role of the opioid system in basal ganglia function, nonselective opioid receptor antagonists have been tested for antidyskinetic efficacy in the clinic (naltrexone and naloxone), although without success. In the current study, ADL5510, a novel, orally active opioid antagonist with mu opioid receptor selectivity, was examined in L-dopa-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaques. Antidyskinetic effects were compared with those of naltrexone. Parkinsonian monkeys with established L-dopa-induced dyskinesia (LID) received acute challenges with L-dopa (subcutaneously) in combination with either vehicle, ADL5510 (0.1, 1, 3 or 10 mg/kg by mouth), or naltrexone (1, 3, or 10 mg/kg subcutaneously). Following treatments, behavior was monitored for 6 hours. Parameters assessed were total activity, parkinsonism, and dyskinesia. ADL5510 (1, 3, and 10 mg/kg) reduced activity and LID (chorea and dystonia) without affecting the antiparkinsonian benefits of L-dopa. The antidyskinetic effect of ADL5510 showed a U-shaped dose-response. It was inactive at 0.1 mg/kg, efficacious at 1 and 3 mg/kg (72% and 40% reductions, respectively), and then less effective at 10 mg/kg. The quality of ON time produced by L-dopa was improved, as indicated by a reduction in the percentage of ON time spent experiencing disabling dyskinesia (70% and 61% reductions with 1 and 3 mg/kg, respectively, compared with L-dopa). Naltrexone, in contrast, did not alleviate LID or affect the antiparkinsonian actions of L-dopa. Mu-selective opioid antagonists have the potential to form the basis of novel antidyskinetic therapies for PD.
Asunto(s)
Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/toxicidad , Antagonistas de Narcóticos/farmacología , Trastornos Parkinsonianos/tratamiento farmacológico , Receptores Opioides mu/antagonistas & inhibidores , Animales , Antiparkinsonianos/toxicidad , Células CHO , Cricetinae , Cricetulus , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Femenino , Humanos , Macaca fascicularis , Masculino , Naltrexona/farmacologíaRESUMEN
A lead optimization campaign in our previously reported sulfamoyl benzamide class of CB(2) agonists was conducted to improve the in vitro metabolic stability profile in this series while retaining high potency and selectivity for the CB(2) receptor. From this study, compound 14, N-(3,4-dimethyl-5-(morpholinosulfonyl)phenyl)-2,2-dimethylbutanamide, was identified as a potent and selective CB(2) agonist exhibiting moderate in vitro metabolic stability and oral bioavailability. Compound 14 demonstrated in vivo efficacy in a rat model of post-surgical pain.
Asunto(s)
Compuestos de Anilina/química , Benzamidas/química , Receptor Cannabinoide CB2/agonistas , Sulfonamidas/química , Compuestos de Anilina/síntesis química , Compuestos de Anilina/farmacocinética , Animales , Benzamidas/síntesis química , Benzamidas/farmacocinética , Humanos , Microsomas Hepáticos/metabolismo , Dolor/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinéticaRESUMEN
A series of imidazopyrimidine derivatives with the general formula I was synthesized and identified as potent inhibitors of iNOS dimer formation, a prerequisite for proper functioning of the enzyme. Stille and Negishi coupling reactions were used as key steps to form the carbon-carbon bond connecting the imidazopyrimidine core to the central cycloalkenyl, cycloalkyl and phenyl ring templates.
RESUMEN
Replacement of the phenyl ring in our previous (morpholinomethyl)aniline carboxamide cannabinoid receptor ligands with a pyridine ring led to the discovery of a novel chemical series of CB2 ligands. Compound 3, that is, 2,2-dimethyl-N-(5-methyl-4-(morpholinomethyl)pyridin-2-yl)butanamide was identified as a potent and selective CB2 agonist exhibiting in vivo efficacy after oral administration in a rat model of neuropathic pain.
Asunto(s)
Aminopiridinas/química , Morfolinas/química , Piridinas/química , Receptor Cannabinoide CB2/agonistas , Administración Oral , Aminopiridinas/síntesis química , Aminopiridinas/farmacología , Animales , Perros , Humanos , Masculino , Microsomas Hepáticos , Morfolinas/síntesis química , Morfolinas/farmacología , Dolor/tratamiento farmacológico , Unión Proteica , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-ActividadRESUMEN
Selective, nonpeptidic delta opioid receptor agonists have been the subject of great interest as potential novel analgesic agents. The discoveries of BW373U86 (1) and SNC80 (2) contributed to the rapid expansion of research in this field. However, poor drug-like properties and low therapeutic indices have prevented clinical evaluation of these agents. Doses of 1 and 2 similar to those required for analgesic activity produce convulsions in rodents and nonhuman primates. Recently, we described a novel series of potent, selective, and orally bioavailable delta opioid receptor agonists. The lead derivative, ADL5859 (4), is currently in phase II proof-of-concept studies for the management of pain. Further structure activity relationship exploration has led to the discovery of ADL5747 (36), which is approximately 50-fold more potent than 4 in an animal model of inflammatory pain. On the basis of its favorable efficacy, safety, and pharmacokinetic profile, 36 was selected as a clinical candidate for the treatment of pain.
Asunto(s)
Analgésicos/farmacología , Analgésicos/uso terapéutico , Benzamidas/farmacología , Benzamidas/uso terapéutico , Benzopiranos/farmacología , Benzopiranos/uso terapéutico , Dolor/tratamiento farmacológico , Receptores Opioides delta/agonistas , Compuestos de Espiro/farmacología , Compuestos de Espiro/uso terapéutico , Analgésicos/administración & dosificación , Analgésicos/química , Animales , Benzamidas/administración & dosificación , Benzamidas/química , Benzopiranos/administración & dosificación , Benzopiranos/química , Células CHO , Ensayos Clínicos como Asunto , Cricetinae , Cricetulus , Cristalografía por Rayos X , Inhibidores del Citocromo P-450 CYP2D6 , Perros , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Hiperalgesia/tratamiento farmacológico , Masculino , Ratas , Ratas Sprague-Dawley , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/químicaRESUMEN
Recently sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Replacing the sulfonamide functionality and reversing the original carboxamide bond led to the discovery of N-(3-(morpholinomethyl)-phenyl)-amides as potent and selective CB(2) agonists. Selective CB(2) agonist 31 (K(i)=2.7; CB(1)/CB(2)=190) displayed robust activity in a rodent model of postoperative pain.
Asunto(s)
Antiinflamatorios/química , Benzamidas/química , Receptor Cannabinoide CB2/agonistas , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Células CHO , Línea Celular , Cricetinae , Cricetulus , Descubrimiento de Drogas , Humanos , Dolor Postoperatorio/tratamiento farmacológico , Ratas , Receptor Cannabinoide CB2/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , TransfecciónRESUMEN
Cyclic tetrapeptide c[Phe-pro-Phe-trp] 2, a diastereomer of CJ-15,208 (1), was identified as a potent dual kappa/mu opioid receptor antagonist devoid of delta opioid receptor affinity against cloned human receptors: K(i) (2)=3.8nM (kappa), 30nM (mu); IC(50) ([(35)S]GTPgammaS binding)=140nM (kappa), 21nM (mu). The d-tryptophan residue rendered 2 ca. eightfold and fourfold more potent at kappa and mu, respectively, than the corresponding l-configured tryptophan in the natural product 1. Phe analogs 3-10, designed to probe the effect of substituents on receptor affinity and selectivity, possessed K(i) values ranging from 14 to 220nM against the kappa opioid receptor with mu/kappa ratios of 0.45-3.0. An alanine scan of 2 yielded c[Ala-pro-Phe-trp] 12, an analog equipotent to 2. Agents 2 and 12 were pure antagonists in vitro devoid of agonist activity. Ac-pro-Phe-trp-Phe-NH(2)16 and Ac-Phe-trp-Phe-pro-NH(2)17 two of the eight possible acyclic peptides derived from 1 and 2, were selective, modestly potent mu ligands: K(i) (16)=340nM (mu); K(i) (17)=360nM (mu).
Asunto(s)
Péptidos Cíclicos/química , Receptores Opioides kappa/antagonistas & inhibidores , Simulación por Computador , Cristalografía por Rayos X , Humanos , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/farmacología , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/antagonistas & inhibidores , Receptores Opioides mu/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Previous research within our laboratories identified sulfamoyl benzamides as novel cannabinoid receptor ligands. Optimization of the amide linkage led to the reverse amide 40. The compound exhibited robust antiallodynic activity in a rodent pain model when administered intraperitoneally. Efficacy after oral administration was observed only when ABT, a cytochrome P450 suicide inhibitor, was coadministered.
Asunto(s)
Benzamidas/farmacología , Receptor Cannabinoide CB2/efectos de los fármacos , Animales , Benzamidas/administración & dosificación , Benzamidas/química , Benzamidas/uso terapéutico , Dolor/tratamiento farmacológico , RoedoresRESUMEN
Selective delta opioid receptor agonists are promising potential therapeutic agents for the treatment of various types of pain conditions. A spirocyclic derivative was identified as a promising hit through screening. Subsequent lead optimization identified compound 20 (ADL5859) as a potent, selective, and orally bioavailable delta agonist. Compound 20 was selected as a clinical candidate for the treatment of pain.
Asunto(s)
Analgésicos/administración & dosificación , Benzamidas/administración & dosificación , Benzopiranos/administración & dosificación , Dolor/tratamiento farmacológico , Receptores Opioides delta/agonistas , Administración Oral , Analgésicos/síntesis química , Analgésicos/química , Animales , Benzamidas/síntesis química , Benzamidas/química , Benzopiranos/síntesis química , Benzopiranos/química , Disponibilidad Biológica , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Humanos , Dosis Máxima Tolerada , Ratones , Estructura Molecular , Actividad Motora/efectos de los fármacos , Dimensión del Dolor/efectos de los fármacos , Ratas , Pruebas de ToxicidadRESUMEN
A series of 2-substituted sulfamoyl arylacetamides of general structure 2 were prepared as potent kappa opioid receptor agonists and the affinities of these compounds for opioid and chimeric receptors were compared with those of dynorphin A. Compounds 2e and 2i were identified as non-peptide small molecules that bound to chimeras 3 and 4 with high affinities similar to dynorphin A, resulting in K(i) values of 1.5 and 1.2 nM and 1.3 and 2.2 nM, respectively.
Asunto(s)
Acetamidas/farmacología , Dinorfinas/farmacología , Receptores Opioides kappa/agonistas , Proteínas Recombinantes de Fusión/agonistas , Acetamidas/síntesis química , Acetamidas/química , Sitios de Unión/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Dinorfinas/química , Estructura Molecular , Peso Molecular , Receptores Opioides kappa/química , Receptores Opioides kappa/genética , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/genética , Bibliotecas de Moléculas Pequeñas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Starting from a screening hit 8 that had modest affinity for the cannabinoid CB(2) receptor, a parallel synthesis approach and initial SAR are described, leading to compound 27 with 120-fold functional selectivity for the CB(2) receptor. This compound produced robust antiallodynic activity in rodent models of postoperative pain and neuropathic pain without traditional cannabinergic side effects.
Asunto(s)
Benzamidas/uso terapéutico , Neuralgia/tratamiento farmacológico , Receptor Cannabinoide CB2/metabolismo , Sulfonamidas/uso terapéutico , Animales , Benzamidas/síntesis química , Benzamidas/farmacología , Sitios de Unión , Relación Dosis-Respuesta a Droga , Ligandos , Ratones , Modelos Animales , Modelos Químicos , Dimensión del Dolor/efectos de los fármacos , Ratas , Receptor Cannabinoide CB2/química , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacologíaRESUMEN
A series of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, mu opioid receptor antagonists, analogs of alvimopan, were prepared using solid phase methodology. This study led to the identification of a highly selective mu opioid receptor antagonist, which interacts selectively with mu peripheral receptors.
Asunto(s)
Sistema Nervioso Central/efectos de los fármacos , Piperidinas/química , Piperidinas/farmacología , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides mu/antagonistas & inhibidores , Administración Oral , Animales , Membrana Celular/metabolismo , Cromatografía Líquida de Alta Presión , Diprenorfina/metabolismo , Tránsito Gastrointestinal/efectos de los fármacos , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Loperamida/farmacología , Ratones , Estructura Molecular , Piperidinas/síntesis química , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Relación Estructura-ActividadRESUMEN
The localization of opioid receptors and their endogenous peptide ligands within the gastrointestinal (GI) tract and their role in the coordination of propulsion and secretion underscores the importance of opioid receptors in the maintenance of GI homeostasis. The peripherally acting micro-opioid receptor antagonists alvimopan and methylnaltrexone (MNTX) are currently under investigation as therapeutic agents to treat the deleterious GI side effects associated with opioid administration. These compounds have demonstrated efficacy in numerous animal models of GI function, and clinical studies have revealed their efficacy in the treatment of postoperative ileus (POI) and opioid-induced bowel dysfunction. Preservation of opioid-mediated analgesia has been demonstrated for these compounds in both the preclinical and clinical settings. Future studies exploring the benefits of selective antagonism of the peripheral mu-opioid receptor in the treatment of other GI conditions may open new therapeutic opportunities for alvimopan and MNTX.
Asunto(s)
Enfermedades Gastrointestinales/tratamiento farmacológico , Tracto Gastrointestinal/efectos de los fármacos , Receptores Opioides mu/antagonistas & inhibidores , Analgésicos Opioides/efectos adversos , Animales , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Enfermedades Gastrointestinales/fisiopatología , Tracto Gastrointestinal/metabolismo , Humanos , Naltrexona/análogos & derivados , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Piperidinas/farmacología , Compuestos de Amonio Cuaternario/farmacología , Receptores Opioides mu/metabolismoRESUMEN
Nitric oxide (NO), a mediator of various physiological and pathophysiological processes, is synthesized by three isozymes of nitric oxide synthase (NOS). Potential candidate clinical drugs should be devoid of inhibitory activity against endothelial NOS (eNOS), since eNOS plays an important role in maintaining normal blood pressure and flow. A new series of aminopiperidines as potent inhibitors of iNOS were identified from a HTS lead. From this study, we identified compound 33 as a potent iNOS inhibitor, with >25-fold selectivity over eNOS and 16-fold selectivity over nNOS.
Asunto(s)
Aminas/síntesis química , Aminas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Piperidinas/síntesis química , Piperidinas/farmacología , Aminas/química , Sitios de Unión , Diseño de Fármacos , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo I/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/metabolismo , Piperidinas/química , Relación Estructura-ActividadRESUMEN
Synthesis, in vitro biological evaluation, and structure-activity relationships of a biaryl cannabinoid mimetic 2 are reported. Variations in the substitution pattern yielded a number of agonists with low nanomolar affinity. Replacing the phenol group by a methyl morpholino acetate group led to compound 28, a 500-fold selective CB(2) receptor agonist.
Asunto(s)
Cannabinoides/química , Cannabinoides/síntesis química , Química Farmacéutica/métodos , Ácidos Carboxílicos/química , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Hidrógeno/química , Enlace de Hidrógeno , Inmunosupresores/química , Concentración 50 Inhibidora , Cinética , Modelos Químicos , Parasimpatolíticos , Fenol/química , Unión ProteicaRESUMEN
A series of opioid peptide ligands containing modified N-terminal tyrosine (Tyr) residues was prepared and evaluated against cloned human mu, delta, and kappa opioid receptors. This work extends the recent discovery that (S)-4-carboxamidophenylalanine (Cpa) is an effective tyrosine bioisostere. Amino acids containing negatively charged functional groups in place of tyrosine's phenolic hydroxyl lacked receptor affinity, while exchange of Tyr for (S)-4-aminophenylalanine was modestly successful. Peptides containing the new amino acids, (S)-4-carboxamido-2,6-dimethylphenylalanine (Cdp) and (S)-beta-(2-aminobenzo[d]thiazol-6-yl)alanine (Aba), displayed binding (K(i)) and functional (EC(50)) profiles comparable to the parent ligands at the three receptors. Cdp represents the best performing Tyr surrogate in terms of overall activity, while Cpa and Aba show a subtle proclivity toward the delta receptor.
Asunto(s)
Química Farmacéutica/métodos , Péptidos/química , Receptores Opioides/química , Tirosina/química , Clonación Molecular , Diseño de Fármacos , Humanos , Enlace de Hidrógeno , Cinética , Ligandos , Modelos Químicos , Conformación Molecular , Receptores Opioides delta/química , Receptores Opioides kappa/química , Receptores Opioides mu/químicaRESUMEN
A novel series of malonamide derivatives was synthesized. These amides were shown to be potent and selective kappa opioid receptor agonists.
Asunto(s)
Química Farmacéutica/métodos , Malonatos/síntesis química , Malonatos/farmacología , Receptores Opioides kappa/antagonistas & inhibidores , Citocromo P-450 CYP2D6/química , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Cinética , Malonatos/química , Modelos Químicos , Conformación MolecularRESUMEN
The series of trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines have been widely investigated as opioid receptor antagonists. One of our research goals was to explore the bioactive conformation of the N-phenethyl trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine derivative 3, prototypical mu-opioid antagonist in this series. In this effort, the rotational degrees of freedom of the N-substituent of 3 were limited by incorporation of an ethylene bridge between the piperidine 2- or 6-position of 3 and the benzylic position of the N-phenethyl moiety. The overall modification led to a novel series of fused bicyclic derivatives of the octahydroquinolizine chemical class, conformationally restricted analogue of 3. The constrained analogues 6 and 9 showed high affinity toward the mu-opioid receptor. Compound 6 was found to be a mu-opioid antagonist, whereas the constrained analogue 9 displayed potent mu-agonist activity in vitro. This study provides additional information about the molecular determinants for mu recognition, the structural features affecting ligand binding, and the structure function relationships.
Asunto(s)
Piperidinas/síntesis química , Receptores Opioides mu/antagonistas & inhibidores , Animales , Células CHO , Cricetinae , Cricetulus , Cristalografía por Rayos X , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Ligandos , Modelos Moleculares , Conformación Molecular , Piperidinas/química , Piperidinas/farmacología , Ensayo de Unión Radioligante , Receptores Opioides mu/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
To better understand structural requirements for a mu ligand of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class to interact with the mu opioid receptor, we have described in the previous article (Le Bourdonnec, B. et al. J. Med. Chem. 2006, 25, 7278-7289) new, constrained analogues of the N-phenethyl derivative 3. One of the active constrained analogues, compound 4, exhibited subnanomolar mu-opioid receptor affinity (K(i) = 0.62 nM) and potent mu-opioid antagonist activity (IC(50) = 0.54 nM). On the basis of structure 4, a new series of mu-opioid receptor antagonists were designed. In these compounds the octahydroquinolizine template of 4 was replaced by an octahydro-1H-pyrido[1,2-a]pyrazine scaffold. The new derivatives were tested for their binding affinities and in vitro functional activity against the cloned human mu-, delta-, and kappa-opioid receptors. From this study, we identified compound 36, which displays high affinity toward the mu-opioid receptor (K(i) = 0.47 nM), potent mu in vitro antagonist activity (IC(50) = 1.8 nM) and improved binding selectivity profile mu/kappa and mu/delta, when compared to 4.
Asunto(s)
Pirazinas/síntesis química , Piridinas/síntesis química , Receptores Opioides mu/antagonistas & inhibidores , Animales , Células CHO , Cricetinae , Cricetulus , Cristalografía por Rayos X , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Ligandos , Estructura Molecular , Pirazinas/química , Pirazinas/farmacología , Piridinas/química , Piridinas/farmacología , Ensayo de Unión Radioligante , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides kappa/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
Structure-activity relationships at the 2alpha-position of the piperidine ring of the trans-4,5-dimethyl-4-(3-hydroxyphenyl)piperidine mu-opioid antagonist series were investigated. This study showed that only small linear alkyl groups (methyl, propyl) are tolerated at the 2alpha-position of the piperidine ring of this series.