RESUMEN
The 5-HT7 receptor is the most recently identified receptor subtype within a family of 5-HT receptors activated by the neurotransmitter serotonin. There has been significant interest in investigating the potential role of this receptor in psychiatric disorders including depression, anxiety, and schizophrenia. Behaviors of 5-HT7 +/+ (wild-type or WT) and 5-HT7 -/- (receptor knockout or KO) mice were compared across 10 different assays (7 for anxiety, 1 for depression, 2 for psychosis) to identify differences that could indicate clinical potential for 5-HT7 receptor antagonism. Evaluation of KO vs. WT mice demonstrated significant differences between the genotypes in the fear conditioning, shock-probe burying, novelty-suppressed feeding, punishment memory, forced swim test, and d-amphetamine hyperactivity assays. There was not consistency in either the direction of behavioral effects across genotypes or across assays. Thus, data from these behavioral assays did not uniformly support the idea that 5-HT7 receptors constitute an important drug target for these psychiatric disorders. The present findings are generally congruent with the mixed results in the literature on the behaviors of 5-HT7 -/-mice and with the data on effects of 5-HT7 receptor antagonists in rodent models that detect activity of anxiolytic, antidepressant, and antipsychotic effects.
Asunto(s)
Ansiedad/tratamiento farmacológico , Depresión/tratamiento farmacológico , Receptores de Serotonina/deficiencia , Esquizofrenia/tratamiento farmacológico , Antagonistas de la Serotonina/uso terapéutico , Animales , Condicionamiento Operante/efectos de los fármacos , Modelos Animales de Enfermedad , Estimulación Eléctrica , Conducta Exploratoria/efectos de los fármacos , Miedo/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Femenino , Fiebre/etiología , Fiebre/terapia , Locomoción/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Noqueados , Castigo , Receptores de Serotonina/genética , Refuerzo en Psicología , Estrés Psicológico/complicaciones , Natación/psicologíaRESUMEN
Identification of ligands that selectively activate the M1 muscarinic signaling pathway has been sought for decades to treat a range of neurological and cognitive disorders. Herein, we describe the optimization efforts focused on addressing key physicochemical and safety properties, ultimately leading to the clinical candidate MK-7622, a highly selective positive allosteric modulator of the M1 muscarinic receptor that has entered Phase II studies in patients with Alzheimer's disease.
RESUMEN
Triazolopyridine ethers with mGlu2 positive allosteric modulator (PAM) activity are disclosed. The synthesis, in vitro activity, and metabolic stability data for a series of analogs is provided. The effort resulted in the discovery of a potent, selective, and brain penetrant lead molecule BMT-133218 ((+)-7m). After oral administration at 10mg/kg, BMT-133218 demonstrated full reversal of PCP-stimulated locomotor activity and prevented MK-801-induced working memory deficits in separate mouse models. Also, reversal of impairments in executive function were observed in rat set-shifting studies at 3 and 10mg/kg (p.o.). Extensive plasma protein binding as the result of high lipophilicity likely limited activity at lower doses. Optimized triazolopyridine ethers offer utility as mGlu2 PAMs for the treatment of schizophrenia and merit further preclinical investigation.
Asunto(s)
Éteres/farmacología , Piridinas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Esquizofrenia/tratamiento farmacológico , Triazoles/farmacología , Administración Oral , Regulación Alostérica/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Éteres/administración & dosificación , Éteres/química , Haplorrinos , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Estructura Molecular , Piridinas/administración & dosificación , Piridinas/química , Ratas , Ratas Sprague-Dawley , Receptores de Glutamato Metabotrópico/metabolismo , Esquizofrenia/metabolismo , Relación Estructura-Actividad , Triazoles/administración & dosificación , Triazoles/químicaRESUMEN
Phosphodiesterase 10A (PDE10A) inhibitors increase the functionality of striatal medium spiny neurons and produce antipsychotic-like effects in rodents by blocking PDE10A mediated hydrolysis of cAMP and/or cGMP. In the current study, we characterized a radiolabeled PDE10A inhibitor, [(3)H]BMS-843496, and developed an ex vivo PDE10 binding autoradiographic assay to explore the relationship between PDE10 binding site occupancy and the observed biochemical and behavioral effects of PDE10 inhibitors in mice. [(3)H]BMS-843496 is a potent PDE10A inhibitor with a binding affinity (KD) of 0.15 nM and a functional selectivity of >100-fold over other PDE subtypes tested. Specific [(3)H]BMS-843496 binding sites were dominant in the basal ganglia, especially the striatum, with low to moderate binding in the cortical and hippocampal areas, of the mouse and monkey brain. Systemic administration of PDE10 inhibitors produced a dose- and plasma/brain concentration-dependent increase in PDE10A occupancy measured in the striatum. PDE10A occupancy was positively correlated with striatal pCREB expression levels. PDE10A occupancy was also correlated with antipsychotic-like effects measured using the conditioned avoidance response model; a minimum of â¼40% occupancy was typically required to achieve efficacy. In contrast, a clear relationship between PDE10A occupancy and catalepsy scores, a potential extrapyramidal symptom readout in rodent, was not evident.
Asunto(s)
Antipsicóticos/farmacología , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Animales , Sitios de Unión , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Macaca fascicularis , Masculino , Ratones , Ratones Noqueados , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/metabolismoRESUMEN
Selective activation of the M1 muscarinic receptor via positive allosteric modulation represents an original approach to treat the cognitive decline in patients with Alzheimer's disease. A series of naphthyl-fused 5-membered lactams were identified as a new class of M1 positive allosteric modulators and were found to possess good potency and in vivo efficacy.
RESUMEN
Selective activation of the M1 muscarinic receptor via positive allosteric modulation represents an approach to treat the cognitive decline in patients with Alzheimer's disease. A series of amides were examined as a replacement for the carboxylic acid moiety in a class of quinolizidinone carboxylic acid M1 muscarinic receptor positive allosteric modulators, and leading pyran 4o and cyclohexane 5c were found to possess good potency and in vivo efficacy.
RESUMEN
One approach to ameliorate the cognitive decline in Alzheimer's disease (AD) has been to restore neuronal signaling from the basal forebrain cholinergic system via the activation of the M(1) muscarinic receptor. A number of nonselective M(1) muscarinic agonists have previously shown positive effects on cognitive behaviors in AD patients, but were limited due to cholinergic adverse events thought to be mediated by the activation of the M(2) to M(5) subtypes. One strategy to confer selectivity for M(1) is the identification of positive allosteric modulators, which would target an allosteric site on the M(1) receptor rather than the highly conserved orthosteric acetylcholine binding site. Quinoline carboxylic acids have been previously identified as highly selective M(1) positive allosteric modulators with good pharmacokinetic and in vivo properties. Herein is described the optimization of a novel quinolizidinone carboxylic acid scaffold with 4-cyanopiperidines being a key discovery in terms of enhanced activity. In particular, modulator 4i gave high plasma free fractions, enhanced central nervous system (CNS) exposure, was efficacious in a rodent in vivo model of cognition, and afforded good physicochemical properties suitable for further preclinical evaluation.
Asunto(s)
Colinérgicos/síntesis química , Nitrilos/síntesis química , Nootrópicos/síntesis química , Piperidinas/síntesis química , Quinolizidinas/síntesis química , Quinolizinas/síntesis química , Receptor Muscarínico M1/fisiología , Regulación Alostérica , Animales , Disponibilidad Biológica , Células CHO , Colinérgicos/química , Colinérgicos/farmacología , Cricetinae , Cricetulus , Miedo/efectos de los fármacos , Humanos , Masculino , Ratones , Nitrilos/química , Nitrilos/farmacología , Nootrópicos/química , Nootrópicos/farmacología , Piperidinas/química , Piperidinas/farmacología , Quinolizidinas/química , Quinolizidinas/farmacología , Quinolizinas/química , Quinolizinas/farmacología , Relación Estructura-ActividadRESUMEN
SAR study of the piperidine moiety in a series of quinolizidinone carboxylic acid M(1) positive allosteric modulators was examined. While the SAR was generally flat, compounds were identified with high CNS exposure to warrant additional in vivo evaluation.
Asunto(s)
Piperidinas/farmacología , Regulación Alostérica , Animales , Células CHO , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Piperidinas/metabolismo , Relación Estructura-ActividadRESUMEN
Fused aromatics such as naphthalene were identified as highly potent and CNS penetrant M(1) positive allosteric modulators during an SAR study to replace the phenyl B-ring linkage.
Asunto(s)
Naftoles/química , Receptor Muscarínico M1/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/sangre , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/líquido cefalorraquídeo , Regulación Alostérica/efectos de los fármacos , Animales , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Humanos , Estructura Molecular , Naftoles/farmacología , Quinolonas/química , Quinolonas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
Incorporation of hydroxycycloalkyl fused pyridone carboxylic acids in lieu of quinolone carboxylic acids enhance free fraction without increased susceptibility to P-glycoprotein transport.
Asunto(s)
Ácidos Carboxílicos/farmacología , Piridonas/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Regulación Alostérica , Animales , Ácidos Carboxílicos/química , Ratones , Transporte de Proteínas , RatasRESUMEN
The phenyl ring in a series of quinolone carboxylic acid M(1) positive allosteric modulators was replaced with a variety of heterocycles in order to reduce protein plasma binding and enhance CNS exposure.
Asunto(s)
Ácidos Carboxílicos/farmacología , Compuestos Heterocíclicos/farmacología , Piridonas/química , Regulación Alostérica , Animales , Proteínas Sanguíneas/química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacocinética , Humanos , RatasRESUMEN
Replacement of a phenyl ring with N-linked heterocycles in a series of quinolone carboxylic acid M1 positive allosteric modulators was investigated. In particular, a pyrazole derivative exhibited improvements in potency, free fraction, and CNS exposure.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Compuestos Heterocíclicos/síntesis química , Pirazoles/síntesis química , Quinolinas/síntesis química , Regulación Alostérica , Animales , Células CHO , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Línea Celular , Cricetinae , Cricetulus , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Humanos , Estructura Molecular , Pirazoles/química , Pirazoles/farmacología , Quinolinas/química , Quinolinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
Positive allosteric modulation of the M1 muscarinic receptor represents an approach to treat the cognitive decline in patients with Alzheimer's disease. Replacement of a quinolone ring system in a quinolone carboxylic acid series of M1 modulators with a quinolizidinone bearing a basic amine linkage led to a series of compounds with higher free fraction, enhanced CNS exposure, and improved efficacy in rodent in vivo models of cognition.
RESUMEN
Synaptic degeneration, including impairment of synaptic plasticity and loss of synapses, is an important feature of Alzheimer disease pathogenesis. Increasing evidence suggests that these degenerative synaptic changes are associated with an accumulation of soluble oligomeric assemblies of amyloid beta (Abeta) known as ADDLs. In primary hippocampal cultures ADDLs bind to a subpopulation of neurons. However the molecular basis of this cell type-selective interaction is not understood. Here, using siRNA screening technology, we identified alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits and calcineurin as candidate genes potentially involved in ADDL-neuron interactions. Immunocolocalization experiments confirmed that ADDL binding occurs in dendritic spines that express surface AMPA receptors, particularly the calcium-impermeable type II AMPA receptor subunit (GluR2). Pharmacological removal of the surface AMPA receptors or inhibition of AMPA receptors with antagonists reduces ADDL binding. Furthermore, using co-immunoprecipitation and photoreactive amino acid cross-linking, we found that ADDLs interact preferentially with GluR2-containing complexes. We demonstrate that calcineurin mediates an endocytotic process that is responsible for the rapid internalization of bound ADDLs along with surface AMPA receptor subunits, which then both colocalize with cpg2, a molecule localized specifically at the postsynaptic endocytic zone of excitatory synapses that plays an important role in activity-dependent glutamate receptor endocytosis. Both AMPA receptor and calcineurin inhibitors prevent oligomer-induced surface AMPAR and spine loss. These results support a model of disease pathogenesis in which Abeta oligomers interact selectively with neurotransmission pathways at excitatory synapses, resulting in synaptic loss via facilitated endocytosis. Validation of this model in human disease would identify therapeutic targets for Alzheimer disease.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Calcineurina/metabolismo , Endocitosis/fisiología , Receptores AMPA/metabolismo , Sinapsis/metabolismo , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/genética , Animales , Calcineurina/genética , Células Cultivadas , Hipocampo/citología , Humanos , Multimerización de Proteína , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores AMPA/química , Receptores AMPA/genética , Sinapsis/patología , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/metabolismoRESUMEN
Incorporation of pyridines and diazines into the biphenyl region of quinolone carboxylic acid derived M(1) positive allosteric modulators was investigated as a means of lowering plasma protein binding to enhance CNS exposure.
Asunto(s)
Proteínas Sanguíneas/química , Piridinas/química , Receptor Muscarínico M1/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Regulación Alostérica , Animales , Proteínas Sanguíneas/metabolismo , Humanos , Unión Proteica , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Receptor Muscarínico M1/metabolismo , Relación Estructura-ActividadRESUMEN
An iterative analog library synthesis approach was employed in the exploration of a quinolone carboxylic acid series of selective M(1) positive allosteric modulators, and strategies for improving potency and plasma free fraction were identified.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Quinolinas/química , Receptor Muscarínico M1/metabolismo , Regulación Alostérica , Animales , Proteínas Sanguíneas/química , Proteínas Sanguíneas/metabolismo , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Humanos , Unión Proteica , Ratas , Bibliotecas de Moléculas PequeñasRESUMEN
The forebrain cholinergic system promotes higher brain function in part by signaling through the M(1) muscarinic acetylcholine receptor (mAChR). During Alzheimer's disease (AD), these cholinergic neurons degenerate, therefore selectively activating M(1) receptors could improve cognitive function in these patients while avoiding unwanted peripheral responses associated with non-selective muscarinic agonists. We describe here benzyl quinolone carboxylic acid (BQCA), a highly selective allosteric potentiator of the M(1) mAChR. BQCA reduces the concentration of ACh required to activate M(1) up to 129-fold with an inflection point value of 845 nM. No potentiation, agonism, or antagonism activity on other mAChRs is observed up to 100 microM. Furthermore studies in M(1)(-/-) mice demonstrates that BQCA requires M(1) to promote inositol phosphate turnover in primary neurons and to increase c-fos and arc RNA expression and ERK phosphorylation in the brain. Radioligand-binding assays, molecular modeling, and site-directed mutagenesis experiments indicate that BQCA acts at an allosteric site involving residues Y179 and W400. BQCA reverses scopolamine-induced memory deficits in contextual fear conditioning, increases blood flow to the cerebral cortex, and increases wakefulness while reducing delta sleep. In contrast to M(1) allosteric agonists, which do not improve memory in scopolamine-challenged mice in contextual fear conditioning, BQCA induces beta-arrestin recruitment to M(1), suggesting a role for this signal transduction mechanism in the cholinergic modulation of memory. In summary, BQCA exploits an allosteric potentiation mechanism to provide selectivity for the M(1) receptor and represents a promising therapeutic strategy for cognitive disorders.
Asunto(s)
Receptor Muscarínico M1/metabolismo , Regulación Alostérica , Secuencia de Aminoácidos , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Células CHO , Señalización del Calcio/efectos de los fármacos , Circulación Cerebrovascular/efectos de los fármacos , Circulación Cerebrovascular/fisiología , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Cricetinae , Cricetulus , Perros , Miedo/efectos de los fármacos , Miedo/fisiología , Humanos , Técnicas In Vitro , Fosfatos de Inositol/metabolismo , Macaca mulatta , Ratones , Ratones Noqueados , Modelos Moleculares , Estructura Terciaria de Proteína , Quinolonas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptor Muscarínico M1/química , Receptor Muscarínico M1/deficiencia , Receptor Muscarínico M1/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sueño/efectos de los fármacos , Sueño/fisiologíaRESUMEN
Age-related learning deficits are often attributed to deterioration of hippocampal function. Conversely, a well studied index of hippocampal activity, the rhythm, is known to enhance hippocampal plasticity and accelerate learning rate in young subjects, suggesting that manipulations of activity might be used as a means to counteract impairments related to the aging process. Here, young and older rabbits were given eyeblink conditioning trials either when exhibiting hippocampal (+) or regardless of hippocampal activity (yoked control). Although, as expected, older-yoked control animals showed a learning deficit, the older + group learned as fast as young controls, demonstrating that aging deficits, at least in eyeblink classical conditioning, can be overcome by giving trials during episodes of hippocampal activity. The use of several learning criteria showed that the benefits of hippocampal occur in multiple phases of learning that may depend on different cognitive or motor processes. Whereas there was a benefit of -triggered training in both age groups during the early phase of acquisition, the enhancement persisted in older animals, peaking during later performance. These findings have implications for theories of age-related memory deficits and may contribute to the development of beneficial treatments.
Asunto(s)
Envejecimiento/psicología , Condicionamiento Palpebral , Hipocampo/fisiopatología , Discapacidades para el Aprendizaje/etiología , Ritmo Teta/psicología , Factores de Edad , Animales , Electrofisiología , ConejosRESUMEN
N-Methyl-D-aspartate (NMDA) antagonists have been demonstrated to suppress the signs of opiate withdrawal; however, side effects limit their clinical use. Since the metabotropic glutamate (mGlu) 5 receptor has been shown to affect glutamate release and modulate NMDA receptor function, we examined the effects of two selective mGlu5 receptor antagonists, 2-methyl-6-(phenyl-ethynyl)-pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), on morphine withdrawal. Pretreatment with MPEP or MTEP (1, 3, and 10 mg/kg, i.p.) significantly attenuated behavioral signs of morphine withdrawal. Specifically, both MPEP and MTEP attenuated the occurrence/severity of chews, digging, salivation, and weight loss, and increased the occurrence of erections. Neither compound changed the occurrence of wet-dog shakes, ptosis, irritability, or lacrimation. Both MPEP and MTEP produced a modest, but significant, attenuation of morphine-withdrawal-induced activation of locus coeruleus neurons in anesthetized rats. These results indicate a role for mGlu5 receptors in morphine withdrawal and suggest the potential for mGlu5 antagonists in the treatment of withdrawal from opiates and other drugs of abuse.
Asunto(s)
Locus Coeruleus/efectos de los fármacos , Morfina/farmacología , Piridinas/uso terapéutico , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Tiazoles/uso terapéutico , Animales , Locus Coeruleus/metabolismo , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor del Glutamato Metabotropico 5 , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/psicología , Tiazoles/farmacologíaRESUMEN
RATIONALE: The depressive phase of bipolar disorder (bipolar depression) is a difficult-to-treat form of depression. The olanzapine/fluoxetine combination (Symbyax) is the only medication approved to treat this disorder. The precise neural mechanisms responsible for its efficacy are not clearly understood. OBJECTIVES: In order to further elucidate the neurobiological mechanisms responsible for the beneficial clinical effects of the olanzapine/fluoxetine combination, the current experiment was designed to investigate the effects of chronic coadministration of olanzapine and fluoxetine on electrophysiological activity in the locus coeruleus (LC). METHODS: Rats received olanzapine for 3 weeks via subcutaneous osmotic pumps while simultaneously receiving daily intraperitoneal injections of fluoxetine. These chronically treated rats were anesthetized, and single-unit recordings of LC neurons were made. RESULTS: Chronic administration of olanzapine alone significantly increased firing of LC neurons, while, as reported previously, chronic administration of fluoxetine alone significantly reduced firing of LC neurons. However, in the combination condition, olanzapine was able to block the fluoxetine-induced suppression of the LC, and a significant increase in LC activity was observed. CONCLUSIONS: The observed increase in firing of LC neurons could lead to enhanced levels of norepinephrine release in projection areas and amelioration of the clinical symptoms of bipolar depression.