RESUMEN
mGlu2/3 Receptors (LY354740) in Anxiety mGlu2/3 receptors when activated decrease glutamate excitation on limbic synapses involved in anxiety. The orally active agonist compound LY354740 (or prodrug LY544344) was active in animal and human models of stress/anxiety. Later clinical studies showed efficacy in generalized anxiety in patients, validating this mechanism clinically. However, the compound was terminated due to rodent seizures in long-term toxicology studies.
Asunto(s)
Ansiedad , Receptores de Glutamato Metabotrópico , Receptores de Glutamato Metabotrópico/agonistas , Humanos , Animales , Ansiedad/tratamiento farmacológico , Ansiolíticos/farmacología , Ansiolíticos/uso terapéutico , Agonistas de Aminoácidos Excitadores/farmacología , Agonistas de Aminoácidos Excitadores/uso terapéutico , Profármacos/farmacología , Compuestos Bicíclicos con PuentesRESUMEN
Layer V pyramidal neurons constitute principle output neurons of the medial prefrontal cortex (mPFC)/neocortex to subcortical regions including the intralaminar/midline thalamic nuclei, amygdala, basal ganglia, brainstem nuclei and the spinal cord. The effects of 5-hydroxytryptamine (5-HT) on layer V pyramidal cells primarily reflect a range of excitatory influences through 5-HT2A receptors and inhibitory influences through non-5-HT2A receptors, including 5-HT1A receptors. While the 5-HT2A receptor is primarily a postsynaptic receptor on throughout the apical dendritic field of 5-HT2A receptors, activation of a minority of 5-HT2A receptors also appears to increase spontaneous excitatory postsynaptic currents/potentials (EPSCs/EPSPs) via a presynaptic effect on thalamocortical terminals arising from the midline and intralaminar thalamic nuclei. Activation of 5-HT2A receptors by the phenethylamine hallucinogen also appears to increase asynchronous release of glutamate upon the layer V pyramidal dendritic field, an effect that is suppressed by 5-HT itself through non-5-HT2A receptors. Serotonergic hallucinogens acting on 5-HT2A receptors also appears to increase gene expression of immediate early genes (iEG) and other receptors appearing to induce an iEG-like response like BDNF. Psychedelic hallucinogens acting on 5-HT2A receptors also induce head twitches in rodents that appear related to induction of glutamate release. These electrophysiological, biochemical and behavioral effects of serotonergic hallucinogens appear to be related to modulating glutamatergic thalamocortical neurotransmission and/or shifting the balance toward 5-HT2A receptor activation and away from non-5-HT2A receptor activation. These 5-HT2A receptor induced responses are modulated by feedback homeostatic mechanisms through mGlu2, mGlu4, and mGlu8 presynaptic receptors on thalamocortical terminals. These 5-HT2A receptor and glutamatergic interactions also appear to play a role on higher cortical functions of the mPFC such as motoric impulsivity and antidepressant-like behavioral responses on the differential-reinforcement-of low rate 72-s (DRL 72-s schedule). These mutually opposing effects between 5-HT2A receptor and mGlu autoreceptor activation (e.g., blocking 5-HT2A receptors and enhancing activity at mGlu2 receptors) may play a clinical role with respect to currently prescribed or novel antidepressant drugs. Thus, there is an important balance between 5-HT2A receptor activation and activation of mGlu autoreceptors on prefrontal cortical layer V pyramidal cells with respect to the electrophysiological, biochemical and behavioral effects serotonergic hallucinogenic drugs.
Asunto(s)
Células Piramidales , Potenciales Postsinápticos Excitadores , Ácido Glutámico , Corteza Prefrontal , SerotoninaRESUMEN
Epidemiological projections of the prevalence of Alzheimer's disease (AD) and related dementias, the rapidly expanding population over the age of 65, and the enormous societal consequence on health, economics, and community foretell of a looming global public health crisis. Currently available treatments for AD are symptomatic, with modest effect sizes and limited impact on longer term disease outcomes. There have been no newly approved pharmaceutical treatments in the last decade, despite enormous efforts to develop disease-modifying treatments directed at Alzheimer's-associated pathology. An unprecedented collaborative effort of government, regulators, industry, academia, and the community at-large is needed to address this crisis and to develop an actionable plan for rapid progress toward successfully developing effective treatments. Here, we map out a course of action in four key priority areas, including (1) addressing the fundamental mechanisms of disease, with the goal of developing a core set of research tools, a framework for data sharing, and creation of accessible validated and replicated disease models; (2) developing translational research that emphasizes rapid progress in disease model development and better translation from preclinical to clinical stages, deploying leading technologies to more accurately develop predictive models; (3) preventing AD through the development of robust methods and resources to advance trials and creating fundamental resources such as continuous adaptive trials, registries, data repositories, and instrument development; and (4) innovating public/private partnerships and global collaborations, with mechanisms to incentivize collaborations and investments, develop larger precompetitive spaces, and more rapid data sharing.
Asunto(s)
Enfermedad de Alzheimer/prevención & control , Enfermedad de Alzheimer/terapia , Investigación Biomédica/tendencias , Investigación Biomédica Traslacional/tendencias , Conducta Cooperativa , HumanosRESUMEN
Group II metabotropic glutamate (mGlu) receptor agonists were efficacious in randomized clinical research trials for schizophrenia and generalized anxiety disorder. The regional quantification of mGlu(2) and mGlu(3) receptors remains unknown. A selective and structurally novel mGlu(2/3) receptor agonist, 2-amino-4-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY459477) was tritiated and the distribution of mGlu(2) and mGlu(3) receptors was studied in transgenic mice lacking either mGlu(2), mGlu(3) or both receptors. LY459477 is an agonist with 1-2 nM potency for rodent and human mGlu(2) and mGlu(3) receptors. The functional selectivity of LY459477 was demonstrated by over 640-fold selectivity and the displacement binding selectivity was greater than 320-fold for all glutamate receptors except mGlu(6) (â¼230-fold). More than 1000-fold selectivity was demonstrated for all non-glutamate receptors known to be targeted by antipsychotic drugs. Like atypical antipsychotic drugs, LY459477 reversed in vitro electrophysiological effects of a serotonergic hallucinogen and behavioral effects of phencyclidine or amphetamine. There was virtually no binding of [(3)H]LY459477 to any brain region in mice with a deletion of both mGlu(2) and mGlu(3) receptors. Regions enriched in mGlu(2) receptors included the medial prefrontal cortex, select hippocampal regions, the medial mammillary nucleus, the medial habenula, and the cerebellar granular cell layer. Regions enriched in mGlu(3) receptors were the dorsolateral entorhinal cortex, the hippocampal CA1 field, the piriform cortex, the substantia nigra, the thalamic reticular nucleus, and primary sensory thalamic nuclei. These findings suggest [(3)H]LY459477 should be a useful tool to further define the role of mGlu(2) and mGlu(3) receptors throughout the brain with respect to major neuropsychiatric syndromes. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
Asunto(s)
Aminoácidos Dicarboxílicos , Encéfalo/metabolismo , Compuestos Bicíclicos con Puentes , Agonistas de Aminoácidos Excitadores , Receptores de Glutamato Metabotrópico/metabolismo , Animales , Células Cultivadas , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , Ratones Noqueados , Ensayo de Unión Radioligante/métodos , Ratas , Receptores de Glutamato Metabotrópico/genética , TritioRESUMEN
The challenges of developing drugs for central nervous system disorders have led some major companies to reduce or discontinue investment in the field, even though the unmet medical need is substantial. How can the wealth of basic research knowledge in neuroscience be successfully translated into new therapies?
Asunto(s)
Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Descubrimiento de Drogas/tendencias , Neurociencias/tendencias , Animales , Enfermedades del Sistema Nervioso Central/metabolismo , Ensayos Clínicos como Asunto/tendencias , Humanos , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/metabolismo , Preparaciones Farmacéuticas/administración & dosificación , Preparaciones Farmacéuticas/metabolismoRESUMEN
Schizophrenia is a disabling psychiatric disorder characterized by positive, negative, and cognitive symptoms. The first pharmacological treatments for schizophrenia were discovered by serendipitous, albeit carefully documented, clinical observations. The discovery of chlorpromazine and other dopamine D2 receptor antagonists as antipsychotic agents set the early course of drug discovery in the context of schizophrenia and other psychiatric disorders, and various monoamine receptors became the prime focus of neuropharmacological studies. Success in treating the positive symptoms nevertheless remained limited by the general lack of efficacy in addressing negative symptoms and cognitive impairment. In recent years, several new experimental approaches have emerged for the identification and treatment of different symptom clusters that do not rely on blockade of monoamine receptors. Muscarinic, nicotinic, and glutamatergic signaling mechanisms have become essential to neuropharmacological and behavioral models of discrete aspects of schizophrenia. And as a consequence of these insights, novel drug entities have become available to study and potentially treat the disabling cognitive and negative symptoms of psychiatric disease. Current attempts to target a new range of receptors entail unprecedented fine-tuning in the pharmacological manipulation of specific receptor subtypes.
Asunto(s)
Antipsicóticos/farmacología , Monoaminas Biogénicas/antagonistas & inhibidores , Esquizofrenia/tratamiento farmacológico , Regulación Alostérica/efectos de los fármacos , Antipsicóticos/química , Antipsicóticos/uso terapéutico , Cognición/efectos de los fármacos , Humanos , Receptores Muscarínicos/metabolismoRESUMEN
(-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039) is a potent and selective group II metabotropic glutamate [(mGlu)2 and mGlu3] receptor agonist for which its prodrug LY2140023 [(1R,4S,5S,6S)-2-thiabicyclo[3.1.0]-hexane-4,6-dicarboxylic acid,4-[(2S)-2-amino-4-(methylthio)-1-oxobutyl]amino-, 2,2-dioxide monohydrate] has recently been shown to have efficacy in the treatment of the positive and negative symptoms of schizophrenia. In this article, we use mGlu receptor-deficient mice to investigate the relative contribution of mGlu2 and mGlu3 receptors in mediating the antipsychotic profile of LY404039 in the phencyclidine (PCP) and d-amphetamine (AMP) models of psychosis. To further explore the mechanism of action of LY404039, we compared the drugs' ability to block PCP-induced hyperlocomotion to that of atypical antipsychotics in wild-type and mice lacking mGlu2/3 receptors. In wild-type animals, LY404039 (3-30 mg/kg i.p.) significantly reversed AMP (5 mg/kg, i.p.)-induced increases in ambulations, distance traveled, and reduced time spent at rest. LY404039 reversed PCP (7.5 mg/kg i.p.)-evoked behaviors at 10 mg/kg. The antipsychotic-like effects of LY404039 (10 mg/kg i.p.) on PCP and AMP-evoked behavioral activation were absent in mGlu2 and mGlu2/3 but not in mGlu3 receptor-deficient mice, indicating that the activation of mGlu2 and not mGlu3 receptors is responsible for the antipsychotic-like effects of the mGlu2/3 receptor agonist LY404039. In contrast, the atypical antipsychotic drugs clozapine and risperidone inhibited PCP-evoked behaviors in both wild-type and mGlu2/3 receptor-deficient mice. These data demonstrate that the antipsychotic-like effects of the mGlu2/3 receptor agonist LY404039 in psychostimulant models of psychosis are mechanistically distinct from those of atypical antipsychotic drugs and are dependent on functional mGlu2 and not mGlu3 receptors.
Asunto(s)
Antipsicóticos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Óxidos S-Cíclicos/farmacología , Receptores de Glutamato Metabotrópico/agonistas , Animales , Evaluación Preclínica de Medicamentos/métodos , Agonistas de Aminoácidos Excitadores/farmacología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Receptores de Glutamato Metabotrópico/fisiologíaRESUMEN
LY354740, a potent and selective mGlu (metabotropic glutamate receptor)2/3 agonist, has shown efficacy in the treatment of generalized anxiety disorder (GAD). LY544344 is a LY354740 prodrug that increases LY354740 bioavailability. This 8-week study was designed to evaluate the efficacy, safety, and tolerability of LY544344 in the treatment of GAD. Participants had a diagnoses of GAD, baseline Hospital Anxiety and Depression Scale anxiety subscale scores > or = 10, and moderate illness severity. Patients were randomized to double-blind treatment with LY544344 16 mg b.i.d. (n = 28), LY544344 8 mg b.i.d. (n = 36), or placebo (n = 44). LY544344 16 mg b.i.d.-treated patients showed significantly greater improvement from baseline in Hamilton Anxiety and Clinical Global Impression-Improvement scores, as well as response and remission rates compared with placebo-treated patients. LY544344 was well tolerated and there were no significant differences in the incidence of treatment-emergent adverse events among the three treatment groups. However, the trial was discontinued early based on findings of convulsions in preclinical studies. In conclusion, the findings of this study support the potential efficacy of mGlu2/3 receptor agonist agents in the treatment of GAD. Additional studies will be needed to further assess the toxicological and clinical profile of LY354740/LY544344.
Asunto(s)
Alanina/análogos & derivados , Trastornos de Ansiedad/tratamiento farmacológico , Compuestos Bicíclicos con Puentes/uso terapéutico , Evaluación de Medicamentos/métodos , Agonistas de Aminoácidos Excitadores/uso terapéutico , Adulto , Alanina/sangre , Alanina/uso terapéutico , Análisis de Varianza , Trastornos de Ansiedad/sangre , Compuestos Bicíclicos con Puentes/sangre , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Escalas de Valoración Psiquiátrica , Resultado del TratamientoRESUMEN
Schizophrenia is a chronic, complex and heterogeneous mental disorder, with pathological features of disrupted neuronal excitability and plasticity within limbic structures of the brain. These pathological features manifest behaviorally as positive symptoms (including hallucinations, delusions and thought disorder), negative symptoms (such as social withdrawal, apathy and emotional blunting) and other psychopathological symptoms (such as psychomotor retardation, lack of insight, poor attention and impulse control). Altered glutamate neurotransmission has for decades been linked to schizophrenia, but all commonly prescribed antipsychotics act on dopamine receptors. LY404039 is a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors and has shown antipsychotic potential in animal studies. With data from rodents, we provide new evidence that mGlu2/3 receptor agonists work by a distinct mechanism different from that of olanzapine. To clinically test this mechanism, an oral prodrug of LY404039 (LY2140023) was evaluated in schizophrenic patients with olanzapine as an active control in a randomized, three-armed, double-blind, placebo-controlled study. Treatment with LY2140023, like treatment with olanzapine, was safe and well-tolerated; treated patients showed statistically significant improvements in both positive and negative symptoms of schizophrenia compared to placebo (P < 0.001 at week 4). Notably, patients treated with LY2140023 did not differ from placebo-treated patients with respect to prolactin elevation, extrapyramidal symptoms or weight gain. These data suggest that mGlu2/3 receptor agonists have antipsychotic properties and may provide a new alternative for the treatment of schizophrenia.
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Antipsicóticos/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Óxidos S-Cíclicos/uso terapéutico , Receptores de Glutamato Metabotrópico/fisiología , Esquizofrenia/tratamiento farmacológico , Animales , Antipsicóticos/toxicidad , Benzodiazepinas/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/toxicidad , Óxidos S-Cíclicos/toxicidad , Modelos Animales de Enfermedad , Método Doble Ciego , Humanos , Olanzapina , Placebos , Receptores de Glutamato Metabotrópico/efectos de los fármacosRESUMEN
Current treatments for depression are less than optimal in terms of onset of action, response and remission rates, and side-effect profiles. Glutamate is the major excitatory neurotransmitter controlling synaptic excitability and plasticity in most brain circuits, including limbic pathways involved in depression. Thus, drugs that target glutamate neuronal transmission offer novel approaches to treat depression. Recently, the NMDA receptor antagonist ketamine has demonstrated clinical efficacy in a randomized clinical trial of depressed patients. Metabotropic glutamate (mGlu) receptors function to regulate glutamate neuronal transmission by altering the release of neurotransmitter or modulating the post-synaptic responses to glutamate. Accumulating evidence from biochemical and behavioral studies support the idea that the regulation of glutamatergic neurotransmission via mGlu receptors is linked to mood disorders and that these receptors may serve as novel targets for the discovery of small molecule modulators with unique antidepressant properties. For example, mGlu receptor modulation can facilitate neuronal stem cell proliferation (neurogenesis) and the release of neurotransmitters that are associated with treatment response to depression in humans (serotonin, norepinephrine, dopamine). In particular, compounds that antagonize mGlu2, mGlu3 and/or mGlu5 receptors (e.g. LY341495, MSG0039, MPEP) have been linked to the above pharmacology and have also shown in vivo activity in animal models predictive of antidepressant efficacy such as the forced-swim test. The in vivo actions of these agents can be antagonized by compounds that block AMPA receptors, suggesting that their actions are direct downstream consequences of the enhancement of glutamate neuronal transmission in brain regions involved in depression. These data provide new approaches to finding mechanistically distinct drugs for depression that may have advantages over current therapies for some patients. Moreover, since the mood disorders encompase a non-homogenous set of symptoms, comorbid disorders, and potential etiologies, the rich arsensel that exists within the mGlu receptor families provides an opportunity for both broad and customized therapeutics.
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Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Trastornos del Humor/tratamiento farmacológico , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Monoaminas Biogénicas/metabolismo , Trastorno Depresivo/tratamiento farmacológico , Ácido Glutámico/fisiología , Humanos , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiologíaRESUMEN
RATIONALE: Data from both preclinical and clinical studies have provided proof of concept that modulation of limbic and forebrain glutamate, via mGlu2/3 receptor agonists, might provide therapeutic benefits in many psychiatric disorders including schizophrenia and anxiety. OBJECTIVE: The aim of this study was to assess the efficacy of a structurally novel, potent, selective mGlu2/3 receptor agonist with improved bioavailability (LY404039) in animal models predictive of antipsychotic and anxiolytic efficacy. MATERIALS AND METHODS: LY404039 was assessed in amphetamine- and phencyclidine-induced hyperlocomotion, conditioned avoidance responding, fear-potentiated startle, marble burying, and rotarod behavioral tests. Monoamine release and turnover were assessed using microdialysis and ex vivo tissue levels. RESULTS: LY404039 attenuated amphetamine- and phencyclidine-induced hyperlocomotion (3-30 and 10 mg/kg, respectively). LY404039 (3-10 mg/kg) inhibited conditioned avoidance responding. LY404039 also reduced fear-potentiated startle in rats (3-30 microg/kg) and marble burying in mice (3-10 mg/kg), indicating anxiolytic-like effects. Importantly, LY404039 did not produce sedative effects or motor impairment as measured by rotarod performance and lack of escape failures in the conditioned avoidance task (at doses up to 30 and 10 mg/kg, respectively). LY404039 (10 mg/kg) also increased dopamine and serotonin release/turnover in the prefrontal cortex. CONCLUSIONS: These results demonstrate the broad preclinical efficacy of LY404039 across multiple animal models of antipsychotic and anxiolytic efficacy. Additionally, this compound modulates mesocortical neurotransmission and provides a novel mechanism for the treatment of psychiatric disorders that may be associated with improved efficacy and reduced incidence of undesirable side effects. As glutamatergic dysfunction has been linked to the etiology of schizophrenia, clinical studies with more potent mGlu2/3 agonists, such as LY404039, may be useful to explore the validity of this hypothesis.
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Conducta Animal/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Óxidos S-Cíclicos/farmacología , Trastornos Mentales/tratamiento farmacológico , Receptores de Glutamato Metabotrópico/agonistas , Aminoácidos/farmacología , Anfetamina/farmacología , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/uso terapéutico , Diazepam/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Masculino , Trastornos Mentales/psicología , Ratones , Estructura Molecular , Actividad Motora/efectos de los fármacos , Fenciclidina/farmacología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Xantenos/farmacologíaRESUMEN
Group II metabotropic glutamate (mGlu) receptor agonists, including (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740) and (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), have demonstrated efficacy in animal models of anxiety and schizophrenia, and LY354740 decreased anxiety in human subjects. Herein, we report the in vitro pharmacological profile and pharmacokinetic properties of another potent, selective, and structurally novel mGlu2/3 receptor agonist, (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039) and provide comparisons with LY354740. Similar to LY354740, LY404039 is a nanomolar potent agonist at recombinant human mGlu2 and mGlu3 receptors (K(i) = 149 and 92, respectively) and in rat neurons expressing native mGlu2/3 receptors (Ki = 88). LY404039 is highly selective for mGlu2/3 receptors, showing more than 100-fold selectivity for these receptors, versus ionotropic glutamate receptors, glutamate transporters, and other receptors targeted by known anxiolytic and antipsychotic medications. Functionally, LY404039 potently inhibited forskolin-stimulated cAMP formation in cells expressing human mGlu2 and mGlu3 receptors. Electrophysiological studies indicated that LY404039 suppressed electrically evoked excitatory activity in the striatum, and serotonin-induced l-glutamate release in the prefrontal cortex; effects reversed by LY341495. These characteristics suggest LY404039 modulates glutamatergic activity in limbic and forebrain areas relevant to psychiatric disorders; and that, similar to LY354740, it works through a mechanism that may be devoid of negative side effects associated with current antipsychotics and anxiolytics. Interestingly, despite the slightly lower potency (approximately 2-5-fold) of LY404039 versus LY354740 in binding, functional, and electrophysiological assays, LY404039 demonstrated higher plasma exposure and better oral bioavailability in pharmacokinetic experiments. Collectively, the current data indicate that LY404039 may be valuable in the treatment of neuropsychiatric disorders, including anxiety and psychosis.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Óxidos S-Cíclicos/farmacología , Óxidos S-Cíclicos/farmacocinética , Agonistas de Aminoácidos Excitadores/farmacología , Agonistas de Aminoácidos Excitadores/farmacocinética , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Animales , Sitios de Unión , Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos con Puentes/farmacocinética , Compuestos Bicíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Línea Celular , Corteza Cerebral/efectos de los fármacos , Colforsina/farmacología , AMP Cíclico/biosíntesis , Óxidos S-Cíclicos/química , Estimulación Eléctrica , Agonistas de Aminoácidos Excitadores/química , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Humanos , Hidrólisis , Técnicas In Vitro , Masculino , Fosfatidilinositoles/metabolismo , Ratas , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Serotonina/farmacología , Antagonistas de la Serotonina/farmacologíaRESUMEN
(-)-4-Amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate (LY389795, (-)-3) is a highly potent and selective agonist of metabotropic glutamate receptors 2 (mGlu2) and 3 (mGlu3). As part of our ongoing research program, we have prepared S-oxidized variants of (-)-3, compounds (-)-10, (+)-11 (LY404040), and (-)-12 (LY404039). Each of these chiral heterobicyclic amino acids displaced specific binding of the mGlu2/3 receptor antagonist 3H-2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid (3H-LY341495) from membranes expressing recombinant human mGlu2 or mGlu3 and acted as potent agonists in cells expressing these receptor subtypes. Docking of the most potent of these derivatives, (+)-11, to mGlu2 revealed the possibility of an additional H-bond interaction between the sulfoxide oxygen of (+)-11 with tyrosine residue Y236. Pharmacokinetic analysis of mGlu active enantiomers (+)-11 and (-)-12 in rats showed each to be well absorbed following oral administration. Consistent with their mGlu2/3 agonist potency and pharmacokinetic properties, both (+)-11 and (-)-12 blocked phencyclidine-evoked ambulations in a dose-dependent manner, indicating their potential as nonclassical antipsychotic agents.
Asunto(s)
Antipsicóticos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Óxidos S-Cíclicos/síntesis química , Receptores de Glutamato Metabotrópico/agonistas , Administración Oral , Animales , Antipsicóticos/química , Antipsicóticos/farmacología , Disponibilidad Biológica , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Cristalografía por Rayos X , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacología , Humanos , Enlace de Hidrógeno , Ligandos , Masculino , Modelos Moleculares , Actividad Motora/efectos de los fármacos , Ensayo de Unión Radioligante , Ratas , Ratas Endogámicas F344 , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
5-Hydroxytryptamine2A (5-HT2A) receptor regulation is atypical compared to most other monoaminergic receptors in that chronic administration of both antagonists and agonists results in down-regulation of cortical 5-HT2A receptor number and the functional in vitro and in vivo effects. We have recently found that midline thalamic lesions, which appeared to block glutamate release induced by activation of 5-HT2A receptors, also increased 5-HT2A receptor binding in layers I and Va of the medial prefrontal cortex (mPFC). These layers contain the highest density of both 5-HT2A receptors and thalamocortical terminals from the midline and intralaminar thalamic nuclei. These findings suggest the hypothesis that excitatory amino acid release plays a role in regulation of postsynaptic 5-HT2A receptors, and that down-regulation of 5-HT2A receptors by 5-HT2A agonists may not be attributed only to simple occupancy of the receptor by direct agonists. Therefore, we examined the effect of a single 30 min pretreatment with the metabotropic glutamate2/3 (mGlu2/3) receptor agonist (1S,2S,5R,6S)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylate monohydrate (LY354740; 10 mg/kg, i.p.) on the second of three consecutive days of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI) treatment (1.25 mg/kg, i.p.). The subchronic DOI administration significantly decreased binding of [125I]DOI to 5-HT2A receptors in layers I and Va of the mPFC by approximately 25%. In contrast, a single dose of LY354740 on Day 2 of this regimen completely blocked the DOI-induced down-regulation. Thus, a presumed hypoglutamatergic state secondary to thalamic lesions and increased glutamate release induced by a subchronic regimen of a 5-HT2A agonist (and hallucinogenic drug) differentially regulate prefrontal cortical 5-HT2A receptor binding.
Asunto(s)
Anfetaminas/farmacología , Compuestos Bicíclicos con Puentes/farmacología , Alucinógenos/farmacología , Corteza Prefrontal/efectos de los fármacos , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Serotonina/metabolismo , Animales , Interacciones Farmacológicas , Masculino , Corteza Prefrontal/metabolismo , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-DawleyRESUMEN
Metabotropic glutamate (mGlu) receptors have been shown to mediate a number of behaviors including emotionality and responsivity to stress as demonstrated by efficacy in preclinical and clinical studies. The objective of this study was to assess the effects of the mGlu2/3 receptor agonist LY404039 (LY) on operant ethanol (EtOH) self-administration during alcohol seeking (pavlovian spontaneous recovery, PSR), alcohol relapse (alcohol deprivation effect, ADE), and maintenance responding for alcohol. Adult alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) and water on a concurrent fixed-ratio 5-fixed-ratio 1 (FR5-FR1) schedule of reinforcement in daily 1h sessions. After at least 10 weeks of daily 1 h sessions, rats underwent seven extinction sessions, followed by 2 weeks of no manipulation, and then rats were tested for the expression of an EtOH PSR for four sessions. Rats were then given a week in their home cage before being returned to the operant chambers with access to EtOH and water (alcohol relapse). Finally, the effects of LY upon maintenance EtOH and water responding were assessed once stable responding was reestablished. The mGlu2/3 receptor agonist LY404039 reduced responding on the EtOH in the PSR test. LY also reduced the expression of an alcohol deprivation effect (ADE) during relapse, but did not reduce EtOH responding under maintenance conditions. The results of this study demonstrate that activating mGlu2/3 receptors inhibits the expression of alcohol seeking and relapse behavior without altering alcohol self-administration behavior.
Asunto(s)
Consumo de Bebidas Alcohólicas/fisiopatología , Conducta Apetitiva/fisiología , Condicionamiento Operante/fisiología , Extinción Psicológica/fisiología , Receptores de Glutamato Metabotrópico/fisiología , Autoadministración , Análisis de Varianza , Animales , Conducta Apetitiva/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Agonistas de Aminoácidos Excitadores/administración & dosificación , Femenino , Masculino , Distribución Aleatoria , Ratas , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Receptores de Glutamato Metabotrópico/agonistas , Refuerzo en PsicologíaRESUMEN
LY354740 is a potent and selective mGlu2/3 receptor agonist with activity in models of psychiatric disorders (anxiety, psychosis), and early clinical studies in anxiety patients. However, the specific receptor subtypes and brain regions which mediate mGlu2/3 receptor agonist pharmacology/efficacy are not well understood. Here we investigate the effects of deleting mGlu2 or mGlu3 receptors on basal and LY354740-regulated c-Fos expression in mouse brain using mGlu2 or mGlu3 knockout mice. Consistent with our earlier findings, LY354740 administration (20 mg/kg, i.p.) to wild-type mice increased c-Fos expression in specific limbic (central amygdala, bed nucleus of the stria terminalis, midline thalamic nuclei) and non-limbic (thalamic dorsolateral geniculate nucleus, superior colliculus, Edinger-Westphal) structures, while modestly suppressing hippocampal c-Fos expression. The LY354740-induced increases in c-Fos expression in all the above regions were abolished by mGlu2, but not mGlu3, receptor deletion. Interestingly, basal c-Fos expression was significantly increased in the hippocampus of mGlu3, but not mGlu2, receptor knockouts compared to wild-type mice. Moreover, this increase was not suppressed by LY354740, such that in the CA3 region LY354740 now increased c-Fos expression in the mGlu3 knockouts. These results demonstrate that the LY354740-induced increases of c-Fos expression in specific brain regions, including the central and extended amygdala are specifically linked to mGlu2 receptors, and LY354740 suppressions of neuronal activity in the hippocampus are linked to mGlu3 receptors.
Asunto(s)
Encéfalo/efectos de los fármacos , Compuestos Bicíclicos con Puentes/farmacología , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/fisiología , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Animales , Encéfalo/anatomía & histología , Encéfalo/metabolismo , Eliminación de Gen , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ratones , Ratones Noqueados , Proteínas Proto-Oncogénicas c-fos/genética , Receptores de Glutamato Metabotrópico/genéticaRESUMEN
Numerous studies have indicated that selective agonists of group II metabotropic glutamate (mGlu) receptors, such as LY354740 [(1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate] and LY379268 [(-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate], may be useful in the treatment of many psychiatric disorders, including psychosis, anxiety, and drug withdrawal. Although animal and human studies demonstrate potential therapeutic utility, poor oral bioavailability is a limiting factor in the clinical development of these compounds. Therefore, a novel prodrug approach is being pursued to increase exposure levels of active compound after oral administration. Here, we demonstrate a 10-fold increase in brain, plasma, and cerebrospinal fluid levels of LY354740 after oral prodrug administration. Furthermore, we compare the oral efficacy of the mGlu2/3 receptor agonist LY354740 and its prodrug LY544344 [(1S,2S,5R,6S)-2-[(2'S)-(2'-amino)propionyl]aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride] in rodent models of psychosis and anxiety. Phencyclidine (PCP)-induced hyperlocomotion was dose dependently inhibited in rats receiving oral administration of 30 or 100 mg/kg LY544344, whereas LY354740 did not significantly reverse PCP-mediated behaviors at doses up to 100 mg/kg. Orally administered LY544344 (30 mg/kg) and subcutaneously administered LY354740 (10 mg/kg) attenuated stress-induced hyperthermia in DBA/2 mice, with the prodrug producing anxiolytic effects at lower oral doses than the parent compound. Although oral administration of LY354740 did not significantly affect fear-induced suppression of operant responding in rats, subcutaneously administered LY354740 (10 or 20 mg/kg) and orally administered LY544344 (10 or 30 mg/kg) produced significant anxiolytic effects in this model. The present data confirm that mGlu2/3 receptor agonists produce antipsychotic and anxiolytic effects in animal behavioral models and demonstrate that oral bioavailability of LY354740 was substantially increased using a prodrug strategy.
Asunto(s)
Conducta Animal/efectos de los fármacos , Compuestos Bicíclicos con Puentes , Profármacos , Receptores de Glutamato Metabotrópico/agonistas , Administración Oral , Alanina/análogos & derivados , Alanina/farmacocinética , Alanina/farmacología , Animales , Disponibilidad Biológica , Temperatura Corporal/efectos de los fármacos , Compuestos Bicíclicos con Puentes/farmacocinética , Compuestos Bicíclicos con Puentes/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos DBA , Actividad Motora/efectos de los fármacos , Profármacos/farmacocinética , Profármacos/farmacología , Ratas , Ratas Sprague-Dawley , Estrés Fisiológico/fisiopatología , Factores de TiempoRESUMEN
Aggregation of the amyloid-beta (Abeta) peptide in the extracellular space of the brain is central to Alzheimer's disease pathogenesis. Abeta aggregation is concentration dependent and brain region specific. Utilizing in vivo microdialysis concurrently with field potential recordings, we demonstrate that Abeta levels in the brain interstitial fluid are dynamically and directly influenced by synaptic activity on a timescale of minutes to hours. Using an acute brain slice model, we show that the rapid effects of synaptic activity on Abeta levels are primarily related to synaptic vesicle exocytosis. These results suggest that synaptic activity may modulate a neurodegenerative disease process, in this case by influencing Abeta metabolism and ultimately region-specific Abeta deposition. The findings also have important implications for treatment development.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Líquido Extracelular/metabolismo , Terminales Presinápticos/metabolismo , Transmisión Sináptica/fisiología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Animales , Exocitosis/fisiología , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Microdiálisis , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/fisiopatología , Técnicas de Cultivo de Órganos , Técnicas de Placa-Clamp , Vía Perforante/fisiología , Placa Amiloide/metabolismo , Transmisión Sináptica/efectos de los fármacos , Vesículas Sinápticas/metabolismoRESUMEN
The synthesis of a series of C3'-cis-substituted carboxycyclopropyl glycines bearing a wide variety of functional groups is described, and the structure-activity relationship for this series as agonists of group II metabotropic glutamate receptors is reported.