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1.
Neuropharmacology ; 186: 108454, 2021 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-33444639

RESUMEN

Positive modulation of cAMP signalling by phosphodiesterase (PDE) inhibitors has recently been explored as a potential target for the reversal of cognitive and behavioural deficits implicating the corticoaccumbal circuit. Previous studies show that PDE type 1 isoform B (PDE1B) inhibition may improve memory function in rodent models; however, the contribution of PDE1B inhibition to impulsivity, attentional and motivational functions as well as its neurophysiological effects have not been investigated. To address this, we recorded single unit activity in medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) in Lister Hooded rats treated with the PDE1B inhibitor Lu AF64386 and tested in the 5-choice serial reaction time task (5-CSRTT). We also asked whether PDE1B inhibition modulates neurophysiological deficits produced by subchronic phencyclidine (PCP) treatment, a rat pharmacological model of schizophrenia. Lu AF64386 significantly affected behavioural parameters consistent with a reduction in goal-directed behaviour, however without affecting accuracy. Additionally, it reduced mPFC neuronal activity. Pre-treatment with PCP did not affect behavioural parameters, however it significantly disrupted overall neuronal firing while increasing phasic responses to reward-predicting cues and disrupting mPFC-NAc cross-talk. The latter two effects were reversed by Lu AF64386. These findings suggest PDE1B inhibition may be beneficial in disorders implicating a dysfunction of the mPFC-NAc network.


Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 1/antagonistas & inhibidores , Objetivos , Fenciclidina/toxicidad , Inhibidores de Fosfodiesterasa/uso terapéutico , Corteza Prefrontal/enzimología , Esquizofrenia/enzimología , Animales , Condicionamiento Operante/efectos de los fármacos , Condicionamiento Operante/fisiología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 1/metabolismo , Modelos Animales de Enfermedad , Femenino , Alucinógenos/toxicidad , Inhibidores de Fosfodiesterasa/farmacología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiopatología , Ratas , Esquizofrenia/inducido químicamente , Esquizofrenia/tratamiento farmacológico
2.
J Org Chem ; 85(9): 5941-5951, 2020 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-32248689

RESUMEN

Two series of novel chiral hexahydro-2H-furo[3,2-b]pyrroles, 4-(7,8-dimethoxyquinazolin-4-yl) series A and 4-(6,7- dimethoxyquinazolin-4-yl) series B, were synthesized in enantiomerically pure form and evaluated for their inhibitory effects on phosphodiesterase 1 (PDE1) and phosphodiesterase 4 (PDE4) as well as for their inhibitory activity on cell proliferation in A375 melanoma and 3T3 fibroblast cells in vitro. Key steps of synthesis were (i) diastereoselective nucleophilic addition of vinylmagnesium bromide to N-allylimine derived from conveniently protected d-glyceraldehyde, (ii) ring-closing metathesis, (iii) debenzylative cycloetherification, and (iv) aromatic nucleophilic substitution. Some of the obtained compounds were proven to be active as inhibitors of PDE1 isoforms, with IC50 values in the high nanomolar/low micromolar concentration range, and showed antiproliferative activity on A375 melanoma cells.


Asunto(s)
Melanoma , Inhibidores de Fosfodiesterasa , Proliferación Celular , Humanos , Melanoma/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas , Pirroles/farmacología , Relación Estructura-Actividad
3.
Cereb Cortex ; 29(12): 5022-5036, 2019 12 17.
Artículo en Inglés | MEDLINE | ID: mdl-30877787

RESUMEN

The calcium-regulated phosphodiesterase 1 (PDE1) family is highly expressed in the brain, but its functional role in neurones is poorly understood. Using the selective PDE1 inhibitor Lu AF64196 and biosensors for cyclic nucleotides including a novel biosensor for cGMP, we analyzed the effect of PDE1 on cAMP and cGMP in individual neurones in brain slices from male newborn mice. Release of caged NMDA triggered a transient increase of intracellular calcium, which was associated with a decrease in cAMP and cGMP in medium spiny neurones in the striatum. Lu AF64196 alone did not increase neuronal cyclic nucleotide levels, but blocked the NMDA-induced reduction in cyclic nucleotides indicating that this was mediated by calcium-activated PDE1. Similar effects were observed in the prefrontal cortex and the hippocampus. Upon corelease of dopamine and NMDA, PDE1 was shown to down-regulate the D1-receptor mediated increase in cAMP. PDE1 inhibition increased long-term potentiation in rat ventral striatum, showing that PDE1 is implicated in the regulation of synaptic plasticity. Overall, our results show that PDE1 reduces cyclic nucleotide signaling in the context of glutamate and dopamine coincidence. This effect could have a therapeutic value for treating brain disorders related to dysfunctions in dopamine neuromodulation.


Asunto(s)
Cuerpo Estriado/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 1/metabolismo , Plasticidad Neuronal/fisiología , Neuronas/metabolismo , Nucleótidos Cíclicos/metabolismo , Animales , Dopamina/metabolismo , Ácido Glutámico/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico/metabolismo , Ratas , Ratas Wistar
4.
J Med Chem ; 62(5): 2798-2813, 2019 03 14.
Artículo en Inglés | MEDLINE | ID: mdl-30763084

RESUMEN

Gabazine, a γ-aminobutyric acid type A (GABAA) receptor antagonist, has previously been reported to inhibit the binding of [3H]NCS-382, a representative ligand of the high-affinity binding site for the neuroactive substance γ-hydroxybutyric acid (GHB). We herein report a study on the structural determinants of gabazine for binding to (i) the orthosteric binding site of the GABAA receptor and (ii) the high-affinity GHB binding site. Expanding the structural diversity of available ligands for the high-affinity GHB binding sites, this study identified 2-(imidazo[1,2- b]pyridazin-2-yl)acetic acid as a novel ligand-scaffold leading to analogues with relatively high affinity ( Ki 0.19-2.19 µM) and >50 times selectivity for the [3H]NCS-382 over [3H]muscimol binding sites. These results highlight that gabazine interacts with the high-affinity GHB and orthosteric GABAA receptor binding sites differently and that distinct analogues can be generated to select between them. To facilitate further in vivo studies, a promising prodrug candidate for brain delivery was identified.


Asunto(s)
Ácido Acético/química , Descubrimiento de Drogas , Hidroxibutiratos/metabolismo , Imidazoles/química , Piridazinas/farmacología , Animales , Sitios de Unión , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Piridazinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
5.
J Med Chem ; 60(21): 9022-9039, 2017 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-29028338

RESUMEN

γ-Hydroxybutyric acid (GHB) is a neuroactive substance with specific high-affinity binding sites. To facilitate target identification and ligand optimization, we herein report a comprehensive structure-affinity relationship study for novel ligands targeting these binding sites. A molecular hybridization strategy was used based on the conformationally restricted 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) and the linear GHB analog trans-4-hydroxycrotonic acid (T-HCA). In general, all structural modifications performed on HOCPCA led to reduced affinity. In contrast, introduction of diaromatic substituents into the 4-position of T-HCA led to high-affinity analogs (medium nanomolar Ki) for the GHB high-affinity binding sites as the most high-affinity analogs reported to date. The SAR data formed the basis for a three-dimensional pharmacophore model for GHB ligands, which identified molecular features important for high-affinity binding, with high predictive validity. These findings will be valuable in the further processes of both target characterization and ligand identification for the high-affinity GHB binding sites.


Asunto(s)
Ácidos Carboxílicos/química , Crotonatos/química , Ciclopentanos/química , Hidroxibutiratos/química , Modelos Moleculares , Sitios de Unión , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/metabolismo , Crotonatos/síntesis química , Crotonatos/metabolismo , Ciclopentanos/síntesis química , Ciclopentanos/metabolismo , Diseño de Fármacos , Ligandos , Conformación Molecular , Relación Estructura-Actividad
6.
Br J Pharmacol ; 174(22): 4186-4198, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28910498

RESUMEN

BACKGROUND AND PURPOSE: PDE1, a subfamily of cyclic nucleotide PDEs consisting of three isoforms, PDE1A, PDE1B and PDE1C, has been implicated in the regulation of vascular tone. The PDE1 isoform(s) responsible for tone regulation is unknown. This study used isoform-preferring PDE1 inhibitors, Lu AF58027, Lu AF64196, Lu AF66896 and Lu AF67897, to investigate the relative contribution of PDE1 isoforms to regulation of vascular tone. EXPERIMENTAL APPROACH: In rat mesenteric arteries, expression and localization of Pde1 isoforms were determined by quantitative PCR and in situ hybridization, and physiological impact of PDE1 inhibition was evaluated by isometric tension recordings. KEY RESULTS: In rat mesenteric arteries, Pde1a mRNA expression was higher than Pde1b and Pde1c. In situ hybridization revealed localization of Pde1a to vascular smooth muscle cells (VSMCs) and only minor appearance of Pde1b and Pde1c. The potency of the PDE1 inhibitors at eliciting relaxation showed excellent correlation with their potency at inhibiting PDE1A. Thus, Lu AF58027 was the most potent at inhibiting PDE1A and was also the most potent at eliciting relaxation in mesenteric arteries. Inhibition of NOS with l-NAME, soluble GC with ODQ or PKG with Rp-8-Br-PET-cGMP all attenuated the inhibitory effect of PDE1 on relaxation, whereas PKA inhibition with H89 had no effect. CONCLUSIONS AND IMPLICATIONS: Pde1a is the dominant PDE1 isoform present in VSMCs, and relaxation mediated by PDE1A inhibition is predominantly driven by enhanced cGMP signalling. These results imply that isoform-selective PDE1 inhibitors are powerful investigative tools allowing examination of physiological and pathological roles of PDE1 isoforms.


Asunto(s)
GMP Cíclico/fisiología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 1/antagonistas & inhibidores , Arterias Mesentéricas/fisiología , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 1/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 1/fisiología , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Isoenzimas/fisiología , Masculino , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/enzimología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/enzimología , Miocitos del Músculo Liso/fisiología , Inhibidores de Fosfodiesterasa/farmacología , Ratas Wistar , Vasodilatación/efectos de los fármacos
7.
Br J Pharmacol ; 174(15): 2563-2575, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28548283

RESUMEN

BACKGROUND AND PURPOSE: The PDE enzymes (PDE1-11) hydrolyse and thus inactivate cyclic nucleotides and are important in the regulation of the cardiovascular system. Here,we have investigated the effects on the cardiovascular system, of two novel selective PDE1 inhibitors, Lu AF41228 and Lu AF58027. EXPERIMENTAL APPROACH: We used rat mesenteric small arteries (internal diameters of 200-300 µm), RT-PCR and measured isometric wall tension. Effects of Lu AF41228 and Lu AF58027 on heart rate and BP were assessed in both anaesthetized and conscious male rats. KEY RESULTS: Nanomolar concentrations of Lu AF41228 and Lu AF58027 inhibited PDE1A, PDE1B and PDE1C enzyme activity, while micromolar concentrations were required to observe inhibitory effects at other PDEs. RT-PCR revealed expression of PDE1A, PDE1B and PDE1C in rat brain, heart and aorta, but only PDE1A and PDE1B in mesenteric arteries. In rat isolated mesenteric arteries contracted with phenylephrine or U46619, Lu AF41228 and Lu AF58027 induced concentration-dependent relaxations which were markedly reduced by inhibitors of guanylate cyclase, ODQ, and adenylate cyclase, SQ22536, and in preparations without endothelium. In anaesthetized rats, Lu AF41228 and Lu AF58027 dose-dependently lowered mean BP and increased heart rate. In conscious rats with telemetric pressure transducers, repeated dosing with Lu AF41228 lowered mean arterial BP 10-15 mmHg and increased heart rate. CONCLUSIONS AND IMPLICATIONS: These novel PDE1 inhibitors induce vasodilation and lower BP, suggesting a potential use of these vasodilators in the treatment of hypertension and vasospasm.


Asunto(s)
Presión Sanguínea/efectos de los fármacos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 1/antagonistas & inhibidores , Inhibidores de Fosfodiesterasa/farmacología , Vasodilatación/efectos de los fármacos , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 1/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Estructura Molecular , Inhibidores de Fosfodiesterasa/química , Ratas , Relación Estructura-Actividad
8.
J Pharmacol Exp Ther ; 361(3): 441-453, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28360333

RESUMEN

Therapeutic interest in augmentation of 5-hydroxytryptamine2A (5-HT2A) receptor signaling has been renewed by the effectiveness of psychedelic drugs in the treatment of various psychiatric conditions. In this study, we have further characterized the pharmacological properties of the recently developed 5-HT2 receptor agonist N-2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine (25CN-NBOH) and three structural analogs at recombinant 5-HT2A, 5-HT2B, and 5-HT2C receptors and investigated the pharmacokinetic properties of the compound. 25CN-NBOH displayed robust 5-HT2A selectivity in [3H]ketanserin/[3H]mesulergine, [3H]lysergic acid diethylamide and [3H]Cimbi-36 binding assays (Ki2C/Ki2A ratio range of 52-81; Ki2B/Ki2A ratio of 37). Moreover, in inositol phosphate and intracellular Ca2+ mobilization assays 25CN-NBOH exhibited 30- to 180-fold 5-HT2A/5-HT2C selectivities and 54-fold 5-HT2A/5-HT2B selectivity as measured by Δlog(Rmax/EC50) values. In an off-target screening 25CN-NBOH (10 µM) displayed either substantially weaker activity or inactivity at a plethora of other receptors, transporters, and kinases. In a toxicological screening, 25CN-NBOH (100 µM) displayed a benign acute cellular toxicological profile. 25CN-NBOH displayed high in vitro permeability (Papp = 29 × 10-6 cm/s) and low P-glycoprotein-mediated efflux in a conventional model of cellular transport barriers. In vivo, administration of 25CN-NBOH (3 mg/kg, s.c.) in C57BL/6 mice mice produced plasma and brain concentrations of the free (unbound) compound of ∼200 nM within 15 minutes, further supporting that 25CN-NBOH rapidly penetrates the blood-brain barrier and is not subjected to significant efflux. In conclusion, 25CN-NBOH appears to be a superior selective and brain-penetrant 5-HT2A receptor agonist compared with (±)-2,5-dimethoxy-4-iodoamphetamine (DOI), and thus we propose that the compound could be a valuable tool for future investigations of physiologic functions mediated by this receptor.


Asunto(s)
Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Agonistas del Receptor de Serotonina 5-HT2/metabolismo , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Animales , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/efectos de los fármacos , Perros , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Células de Riñón Canino Madin Darby , Masculino , Ratones , Ratones Endogámicos C57BL , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Agonistas del Receptor de Serotonina 5-HT2/química
9.
ChemMedChem ; 11(20): 2299-2310, 2016 10 19.
Artículo en Inglés | MEDLINE | ID: mdl-27620323

RESUMEN

The ρ-containing γ-aminobutyric acid type A receptors (GABAA Rs) play an important role in controlling visual signaling. Therefore, ligands that selectively target these GABAA Rs are of interest. In this study, we demonstrate that the partial GABAA R agonist imidazole-4-acetic acid (IAA) is able to penetrate the blood-brain barrier in vivo; we prepared a series of α- and N-alkylated, as well as bicyclic analogues of IAA to explore the structure-activity relationship of this scaffold focusing on the acetic acid side chain of IAA. The compounds were prepared via IAA from l-histidine by an efficient minimal-step synthesis, and their pharmacological properties were characterized at native rat GABAA Rs in a [3 H]muscimol binding assay and at recombinant human α1 ß2 γ2S and ρ1  GABAA Rs using the FLIPR™ membrane potential assay. The (+)-α-methyl- and α-cyclopropyl-substituted IAA analogues ((+)-6 a and 6 c, respectively) were identified as fairly potent antagonists of the ρ1  GABAA R that also displayed significant selectivity for this receptor over the α1 ß2 γ2S GABAA R. Both 6 a and 6 c were shown to inhibit GABA-induced relaxation of retinal arterioles from porcine eyes.


Asunto(s)
Descubrimiento de Drogas , Imidazoles/farmacología , Receptores de GABA-A/metabolismo , Vasos Retinianos/efectos de los fármacos , Animales , Arteriolas/efectos de los fármacos , Arteriolas/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , Ojo/efectos de los fármacos , Humanos , Imidazoles/administración & dosificación , Imidazoles/química , Ratones , Estructura Molecular , Vasos Retinianos/metabolismo , Relación Estructura-Actividad , Porcinos
10.
ACS Chem Neurosci ; 7(11): 1614-1619, 2016 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-27564969

RESUMEN

The toxic hallucinogen 25B-NBOMe is very rapidly degraded by human liver microsomes and has low oral bioavailability. Herein we report on the synthesis, microsomal stability, and 5-HT2A/5-HT2C receptor profile of novel analogues of 25B-NBOMe modified at the primary site of metabolism. Although microsomal stability could be increased while maintaining potent 5-HT2 receptor agonist properties, all analogues had an intrinsic clearance above 1.3 L/kg/h predictive of high first-pass metabolism.


Asunto(s)
Fenetilaminas/farmacología , Fenetilaminas/farmacocinética , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Agonistas del Receptor de Serotonina 5-HT2/farmacocinética , Anisoles/química , Línea Celular , Evaluación Preclínica de Medicamentos , Estabilidad de Medicamentos , Células HEK293 , Alucinógenos/química , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Fenetilaminas/síntesis química , Fenetilaminas/química , Receptor de Serotonina 5-HT2A/genética , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2C/genética , Receptor de Serotonina 5-HT2C/metabolismo , Agonistas del Receptor de Serotonina 5-HT2/síntesis química , Estereoisomerismo , Relación Estructura-Actividad
11.
J Pharmacol Exp Ther ; 354(2): 166-74, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25986445

RESUMEN

γ-Hydroxybutyric acid (GHB) is a recreational drug, a clinically prescribed drug in narcolepsy and alcohol dependence, and an endogenous substance that binds to both high- and low-affinity sites in the brain. For studying the molecular mechanisms and the biologic role of the GHB high-affinity binding sites, ligands with high and specific affinity are essential. The conformationally restricted GHB analog HOCPCA (3-hydroxycyclopent-1-enecarboxylic acid) is one such compound. The objective of this study was to investigate the transport of HOCPCA across the blood-brain barrier in vitro and in vivo and to investigate the hypothesis that HOCPCA, like GHB, is a substrate for the monocarboxylate transporters (MCTs). For in vitro uptake studies, MCT1, -2, and -4 were recombinantly expressed in Xenopus laevis oocytes, and the previously reported radioligand [(3)H]HOCPCA was used as substrate. HOCPCA inhibited the uptake of the endogenous MCT substrate l-[(14)C]lactate, and [(3)H]HOCPCA was shown to act as substrate for MCT1 and 2 (Km values in the low- to mid-millimolar range). Introducing single-point amino acid mutations into positions essential for MCT function supported that HOCPCA binds to the endogenous substrate pocket of MCTs. MCT1-mediated brain entry of HOCPCA (10 mg/kg s.c.) was further confirmed in vivo in mice by coadministration of increasing doses of the MCT inhibitor AR-C141990 [(R)-5-(3-hydroxypyrrolidine-1-carbonyl)-1-isobutyl-3-methyl-6-(quinolin-4-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione], which inhibited brain penetration of HOCPCA in a dose-dependent manner (ID50 = 4.6 mg/kg). Overall, our study provides evidence that MCT1 is an important brain entry site for HOCPCA and qualifies for future in vivo studies with HOCPCA.


Asunto(s)
Encéfalo/metabolismo , Ácidos Carboxílicos/metabolismo , Ciclopentanos/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Oxibato de Sodio/análogos & derivados , Oxibato de Sodio/metabolismo , Simportadores/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Ácidos Carboxílicos/química , Ciclopentanos/química , Perros , Humanos , Células de Riñón Canino Madin Darby , Masculino , Ratones , Ratas , Xenopus laevis
12.
Eur J Med Chem ; 84: 181-93, 2014 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-25016376

RESUMEN

Novel pyrazolo[5,1-f][1,6]naphthyridines, pyrazolo[5,1-a][2,6]naphthyridines, pyrazolo[5,1-a][2,7]naphthyridines and pyrazolo[5,1-a]isoquinolines phenylimidazole/benzimidazole ethylene-linked were designed and synthesized for PDE10A interaction. An AgOTf and proline-cocatalyzed multicomponent methodology based on use of o-alkynylaldehydes, tosylhydrazide and ketones was developed and proved to be a convenient route for assembly of most of the novel tricyclic pyrazoles synthesized. Pyrazolo[5,1-f][1,6]naphthyridine 43 and 59, pyrazolo[5,1-a][2,6]naphthyridine 66, and pyrazolo[5,1-a][2,7]naphthyridine 42 showed the highest affinity for PDE10A enzyme (IC50 = 40, 42, 40, 55 nM, respectively).


Asunto(s)
Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Pirazoles/farmacología , Animales , Relación Dosis-Respuesta a Droga , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Inhibidores de Fosfodiesterasa/química , Pirazoles/síntesis química , Pirazoles/química , Ratas , Relación Estructura-Actividad
13.
J Nucl Med ; 55(9): 1513-8, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24994928

RESUMEN

UNLABELLED: Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling, and several pharmaceutical companies currently investigate PDE10A inhibitors in clinical trials for various central nervous system diseases. A PDE10A PET ligand may provide evidence that a clinical drug candidate reaches and binds to the target. Here we describe the successful discovery and initial validation of the novel radiolabeled PDE10A ligand 5,8-dimethyl-2-[2-((1-(11)C-methyl)-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine ((11)C-Lu AE92686) and its tritiated analog (3)H-Lu AE92686. METHODS: Initial in vitro experiments suggested Lu AE92686 as a promising radioligand, and the corresponding tritiated and (11)C-labeled compounds were synthesized. (3)H-Lu AE92686 was evaluated as a ligand for in vivo occupancy studies in mice and rats, and (11)C-Lu AE92686 was evaluated as a PET tracer candidate in cynomolgus monkeys and in humans. RESULTS: (11)C-Lu AE92686 displayed high specificity and selectivity for PDE10A-expressing regions in the brain of cynomolgus monkeys and humans. Similar results were found in rodents using (3)H-Lu AE92686. The binding of (11)C-Lu AE92686 and (3)H-Lu AE92686 to striatum was completely and dose-dependently blocked by the structurally different PDE10A inhibitor 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (MP-10) in rodents and in monkeys. In all species, specific binding of the radioligand was seen in the striatum but not in the cerebellum, supporting the use of the cerebellum as a reference region. The binding potentials (BPND) of (11)C-Lu AE92686 in the striatum of both cynomolgus monkeys and humans were evaluated by the simplified reference tissue model with the cerebellum as the reference tissue, and BPND was found to be high and reproducible-that is, BPNDs were 6.5 ± 0.3 (n = 3) and 7.5 ± 1.0 (n = 12) in monkeys and humans, respectively. CONCLUSION: Rodent, monkey, and human tests of labeled Lu AE92686 suggest that (11)C-Lu AE92686 has great potential as a human PET tracer for the PDE10A enzyme.


Asunto(s)
Encéfalo , Radioisótopos de Carbono , Inhibidores de Fosfodiesterasa , Hidrolasas Diéster Fosfóricas , Tomografía de Emisión de Positrones , Radiofármacos , Adulto , Femenino , Humanos , Masculino , Ratas , Encéfalo/enzimología , Cromatografía Líquida de Alta Presión , Ligandos , Macaca fascicularis , Hidrolasas Diéster Fosfóricas/análisis , Ratas Sprague-Dawley , Animales
14.
PLoS One ; 9(6): e100209, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24956197

RESUMEN

The voltage-gated potassium channels of the KV7 family (KV7.1-5) play important roles in controlling neuronal excitability and are therefore attractive targets for treatment of CNS disorders linked to hyperexcitability. One of the main challenges in developing KV7 channel active drugs has been to identify compounds capable of discriminating between the neuronally expressed subtypes (KV7.2-5), aiding the identification of the subunit composition of KV7 currents in various tissues, and possessing better therapeutic potential for particular indications. By taking advantage of the structure-activity relationship of acrylamide KV7 channel openers and the effects of these compounds on mutant KV7 channels, we have designed and synthesized a novel KV7 channel modulator with a unique profile. The compound, named SMB-1, is an inhibitor of KV7.2 and an activator of KV7.4. SMB-1 inhibits KV7.2 by reducing the current amplitude and increasing the time constant for the slow component of the activation kinetics. The activation of KV7.4 is seen as an increase in the current amplitude and a slowing of the deactivation kinetics. Experiments studying mutant channels with a compromised binding site for the KV7.2-5 opener retigabine indicate that SMB-1 binds within the same pocket as retigabine for both inhibition of KV7.2 and activation of KV7.4. SMB-1 may serve as a valuable tool for KV7 channel research and may be used as a template for further design of better subtype selective KV7 channel modulators. A compound with this profile could hold novel therapeutic potential such as the treatment of both positive and cognitive symptoms in schizophrenia.


Asunto(s)
Canales de Potasio KCNQ , Canal de Potasio KCNQ2 , Moduladores del Transporte de Membrana/química , Moduladores del Transporte de Membrana/farmacología , Mutación Missense , Sustitución de Aminoácidos , Animales , Humanos , Canales de Potasio KCNQ/agonistas , Canales de Potasio KCNQ/antagonistas & inhibidores , Canales de Potasio KCNQ/genética , Canales de Potasio KCNQ/metabolismo , Canal de Potasio KCNQ2/agonistas , Canal de Potasio KCNQ2/antagonistas & inhibidores , Canal de Potasio KCNQ2/genética , Canal de Potasio KCNQ2/metabolismo , Xenopus laevis
15.
J Med Chem ; 57(13): 5823-8, 2014 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-24878269

RESUMEN

By introducing distal substituents on a tetracyclic scaffold resembling the ergoline structure, two series of analogues were achieved exhibiting subnanomolar receptor binding affinities for the dopamine D2 and serotonin 5-HT6 receptor subtype, respectively. While the 5-HT6 ligands were antagonists, the D2 ligands displayed intrinsic activities ranging from full agonism to partial agonism with low intrinsic activity. These structures could potentially be interesting for treatment of neurological diseases such as schizophrenia, Parkinson's disease, and cognitive deficits.


Asunto(s)
Ergolinas/química , Receptores de Dopamina D2/agonistas , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/química , Humanos , Ligandos , Receptores de Dopamina D2/química , Receptores de Serotonina/química
16.
Neurochem Res ; 39(10): 2018-23, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24519542

RESUMEN

2,5-Dimethoxyphenethylamines and their N-benzylated derivatives are potent 5-HT2A agonists with psychedelic effects in humans. The N-benzylated derivatives are among the most selective 5-HT2A agonists currently available and their usage as biochemical and brain imaging tools is increasing, yet very little is known about the relationships between the structure of the ligands and their pharmacokinetic profile. In order to evaluate the potential of these compounds for in vivo applications we have determined the microsomal stability of 11 phenethylamines and 27 N-benzylated derivatives thereof using human liver microsomes. We found that the N-benzylated phenethylamines have much higher intrinsic clearance than the parent phenethylamines. We hypothesize that their low hepatic stability renders them orally inactive due to first pass metabolism, which is supported by anecdotal data from recreational use of these compounds.


Asunto(s)
Receptor de Serotonina 5-HT2A/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacocinética , Administración Oral , Disponibilidad Biológica , Humanos
17.
J Med Chem ; 56(20): 8201-5, 2013 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-24053696

RESUMEN

3-Hydroxycyclopent-1-enecarboxylic acid (HOCPCA, 1) is a potent ligand for the high-affinity GHB binding sites in the CNS. An improved synthesis of 1 together with a very efficient synthesis of [(3)H]-1 is described. The radiosynthesis employs in situ generated lithium trimethoxyborotritide. Screening of 1 against different CNS targets establishes a high selectivity, and we demonstrate in vivo brain penetration. In vitro characterization of [(3)H]-1 binding shows high specificity to the high-affinity GHB binding sites.


Asunto(s)
Ácidos Carboxílicos/metabolismo , Sistema Nervioso Central/metabolismo , Ciclopentanos/metabolismo , Hidroxibutiratos/metabolismo , Animales , Benzocicloheptenos/química , Benzocicloheptenos/metabolismo , Sitios de Unión , Unión Competitiva , Encéfalo/metabolismo , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Línea Celular , Ciclopentanos/síntesis química , Ciclopentanos/química , Estabilidad de Medicamentos , Hidroxibutiratos/química , Cinética , Ligandos , Masculino , Modelos Químicos , Estructura Molecular , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Membranas Sinápticas/metabolismo , Tritio/metabolismo , Ácido gamma-Aminobutírico/química , Ácido gamma-Aminobutírico/metabolismo
18.
Bioorg Med Chem ; 21(19): 6053-62, 2013 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-23978358

RESUMEN

PDE10A is a recently identified phosphodiesterase with a quite remarkable localization since the protein is abundant only in brain tissue. Based on this unique localization, research has focused extensively on using PDE10A modulators as a novel therapeutic approach for dysfunction in the basal ganglia circuit including Parkinson's disease, Huntington's disease, schizophrenia, addiction and obsessive compulsive disorder. Medicinal chemistry efforts identified the N-methyl-N-[4-(quinolin-2-ylmethoxy)-phenyl]-isonicotinamide (8) as a nanomolar PDE10A inhibitor. A subsequent Lead-optimization program identified analogous N-methylanilides and their corresponding N-methylbenzamides (29) as potent PDE10A inhibitors, concurrently some interesting and unexpected binding modes were identified.


Asunto(s)
Anilidas/síntesis química , Benzamidas/síntesis química , Inhibidores de Fosfodiesterasa/síntesis química , Anilidas/química , Anilidas/farmacología , Benzamidas/química , Benzamidas/farmacología , Cristalografía por Rayos X , Activación Enzimática/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Relación Estructura-Actividad
19.
J Med Chem ; 56(3): 993-1006, 2013 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-23294161

RESUMEN

A series of bioisosteric 4-(aminomethyl)-1-hydroxypyrazole (4-AHP) analogues of muscimol, a GABA(A) receptor agonist, has been synthesized and pharmacologically characterized at native and selected recombinant GABA(A) receptors. The unsubstituted 4-AHP analogue (2a) (EC(50) 19 µM, R(max) 69%) was a moderately potent agonist at human α(1)ß(2)γ(2) GABA(A) receptors, and in SAR studies substitutions in the 3- and/or 5-position were found to be detrimental to binding affinities. Ligand-receptor docking in an α(1)ß(2)γ(2) GABA(A) receptor homology model along with the obtained SAR indicate that 2a and muscimol share a common binding mode, which deviates from the binding mode of the structurally related antagonist series based on 4-(piperidin-4-yl)-1-hydroxypyrazole (4-PHP, 1). Selectivity for α(1)ß(2)γ(2) over ρ(1) GABA(A) receptors was observed for the 5-chloro, 5-bromo, and 5-methyl substituted analogues of 2a illustrating that even small differences in structure can give rise to subtype selectivity.


Asunto(s)
Agonistas de Receptores de GABA-A/farmacología , Muscimol/análogos & derivados , Simulación por Computador , Agonistas de Receptores de GABA-A/síntesis química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Muscimol/síntesis química , Muscimol/farmacología , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-Actividad
20.
Expert Opin Ther Pat ; 23(1): 31-45, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23210904

RESUMEN

INTRODUCTION: Inhibitors of the phosphodiesterase enzyme PDE10A have been the target for extensive investigations and huge drug discovery research efforts during the recent years. Although PDE10A with its 13 years history is a relatively newly discovered target, it has been paradigmatic for the new generation of 'high efficiency drug discovery'. Several companies now have clinical programs aiming at validating the clinical potential of PDE10A inhibitors. The majority of companies have been focusing on the treatment of schizophrenia since preclinical evidence suggests that a PDE10A inhibitor could provide antipsychotic, pro-cognitive and negative symptom efficacy. AREAS COVERED: This article highlights and reviews research advances published in the patent literature since mid-2009 until mid-2012. The article is supplemented with selected publications from the scientific literature, emphasizing the possible involvement of PDE10A inhibitors in the treatment of schizophrenia. EXPERT OPINION: Several compounds from various companies are currently undergoing clinical testing, dominated by compounds in clinical Phase I. Focus is mainly on CNS diseases and schizophrenia is the leading target indication.


Asunto(s)
Diseño de Fármacos , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/efectos de los fármacos , Animales , Antipsicóticos/farmacología , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Enfermedades del Sistema Nervioso Central/fisiopatología , Cognición/efectos de los fármacos , Humanos , Patentes como Asunto , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/fisiopatología
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