Assuntos
Azepinas/uso terapêutico , Antagonistas dos Receptores de Orexina/uso terapêutico , Medicamentos Indutores do Sono/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Triazóis/uso terapêutico , Animais , Azepinas/efeitos adversos , Azepinas/química , Azepinas/farmacologia , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Antagonistas dos Receptores de Orexina/efeitos adversos , Antagonistas dos Receptores de Orexina/química , Antagonistas dos Receptores de Orexina/farmacologia , Medicamentos Indutores do Sono/efeitos adversos , Medicamentos Indutores do Sono/química , Medicamentos Indutores do Sono/farmacologia , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Triazóis/efeitos adversos , Triazóis/química , Triazóis/farmacologiaRESUMO
Screening of a fragment library for PDE10A inhibitors identified a low molecular weight pyrimidine hit with PDE10A Ki of 8700 nM and LE of 0.59. Initial optimization by catalog followed by iterative parallel synthesis guided by X-ray cocrystal structures resulted in rapid potency improvements with minimal loss of ligand efficiency. Compound 15 h, with PDE10A Ki of 8.2 pM, LE of 0.49, and >5000-fold selectivity over other PDEs, fully attenuates MK-801-induced hyperlocomotor activity after ip dosing.
Assuntos
Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Relação Estrutura-Atividade , Animais , Técnicas de Química Sintética , Cristalografia por Raios X , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Masculino , Inibidores de Fosfodiesterase/síntese química , Diester Fosfórico Hidrolases/química , Diester Fosfórico Hidrolases/metabolismo , Pirimidinas/química , Ratos Wistar , Esquizofrenia/tratamento farmacológicoRESUMO
Phosphodiesterase 10A (PDE10A) has garnered attention as a potential therapeutic target for schizophrenia due to its prominent striatal expression and ability to modulate striatal signaling. The present study used the selective PDE10A inhibitor MP-10 and the dopamine D2 antagonist haloperidol to compare effects of PDE10A inhibition and dopamine D2 blockade on striatopallidal (D2) and striatonigral (D1) pathway activation. Our studies confirmed that administration of MP-10 significantly elevates expression of the immediate early genes (IEG) c-fos, egr-1, and arc in rat striatum. Furthermore, we demonstrated that MP-10 induced egr-1 expression was distributed evenly between enkephalin-containing D2-neurons and substance P-containing D1-neurons. In contrast, haloperidol (3 mg/kg) selectively activated egr-1 expression in enkephalin neurons. Co-administration of MP-10 and haloperidol (0.5 mg/kg) increased IEG expression to a greater extent than either compound alone. Similarly, in a rat catalepsy assay, administration of haloperidol (0.5 mg/kg) or MP-10 (3-30 mg/kg) did not produce cataleptic behavior when dosed alone, but co-administration of haloperidol with MP-10 (3 and 10 mg/kg) induced cataleptic behaviors. Interestingly, co-administration of haloperidol with a high dose of MP-10 (30 mg/kg) failed to produce cataleptic behavior. These findings are important for understanding the neural circuits involved in catalepsy and suggest that the behavioral effects produced by PDE10A inhibitors may be influenced by concomitant medication and the level of PDE10A inhibition achieved by the dose of the inhibitor.
Assuntos
Catalepsia/induzido quimicamente , Corpo Estriado/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Haloperidol/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Pirazóis/farmacologia , Quinolinas/farmacologia , Animais , Catalepsia/metabolismo , Corpo Estriado/metabolismo , Proteínas do Citoesqueleto/metabolismo , Relação Dose-Resposta a Droga , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Encefalinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Masculino , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Sprague-Dawley , Ratos Wistar , Receptores de Dopamina D2/metabolismo , Substância P/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismoRESUMO
Highly selective orexin receptor antagonists (SORAs) of the orexin 2 receptor (OX2R) have become attractive targets both as potential therapeutics for insomnia as well as biological tools to help further elucidate the underlying pharmacology of the orexin signaling pathway. Herein, we describe the discovery of a novel piperidine ether 2-SORA class identified by systematic lead optimization beginning with filorexant, a dual orexin receptor antagonist (DORA) that recently completed Phase 2 clinical trials. Changes to the ether linkage and pendant heterocycle of filorexant were found to impart significant selectivity for OX2R, culminating in lead compound PE-6. PE-6 displays sub-nanomolar binding affinity and functional potency on OX2R while maintaining >1600-fold binding selectivity and >200-fold functional selectivity versus the orexin 1 receptor (OX1R). PE-6 bears a clean off-target profile, a good overall preclinical pharmacokinetic (PK) profile, and reduces wakefulness with increased NREM and REM sleep when evaluated in vivo in a rat sleep study. Importantly, subtle structural changes to the piperidine ether class impart dramatic changes in receptor selectivity. To this end, our laboratories have identified multiple piperidine ether 2-SORAs, 1-SORAs, and DORAs, providing access to a number of important biological tool compounds from a single structural class.
Assuntos
Éteres/química , Antagonistas dos Receptores de Orexina , Piperidinas/química , Pirimidinas/química , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Éteres/síntese química , Éteres/farmacocinética , Meia-Vida , Humanos , Receptores de Orexina/metabolismo , Piperidinas/metabolismo , Ligação Proteica , Pirimidinas/metabolismo , Ratos , Sono/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Slow waves represent one of the prominent EEG signatures of non-rapid eye movement (non-REM) sleep and are thought to play an important role in the cellular and network plasticity that occurs during this behavioral state. These slow waves of natural sleep are currently considered to be exclusively generated by intrinsic and synaptic mechanisms within neocortical territories, although a role for the thalamus in this key physiological rhythm has been suggested but never demonstrated. Combining neuronal ensemble recordings, microdialysis, and optogenetics, here we show that the block of the thalamic output to the neocortex markedly (up to 50%) decreases the frequency of slow waves recorded during non-REM sleep in freely moving, naturally sleeping-waking rats. A smaller volume of thalamic inactivation than during sleep is required for observing similar effects on EEG slow waves recorded during anesthesia, a condition in which both bursts and single action potentials of thalamocortical neurons are almost exclusively dependent on T-type calcium channels. Thalamic inactivation more strongly reduces spindles than slow waves during both anesthesia and natural sleep. Moreover, selective excitation of thalamocortical neurons strongly entrains EEG slow waves in a narrow frequency band (0.75-1.5 Hz) only when thalamic T-type calcium channels are functionally active. These results demonstrate that the thalamus finely tunes the frequency of slow waves during non-REM sleep and anesthesia, and thus provide the first conclusive evidence that a dynamic interplay of the neocortical and thalamic oscillators of slow waves is required for the full expression of this key physiological EEG rhythm.
Assuntos
Potenciais de Ação/fisiologia , Neurônios/fisiologia , Sono/fisiologia , Tálamo/fisiologia , Animais , Canais de Cálcio Tipo T/metabolismo , Córtex Cerebral/fisiologia , Eletroencefalografia , Masculino , Ratos , Ratos WistarRESUMO
The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to the wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX1R/OX2R) orexin receptor antagonists. However, elucidation of the pharmacology associated with selective orexin-2 receptor antagonists (2-SORAs) has been hampered by the lack of orally bioavailable, highly selective small molecule probes. Herein, the discovery and optimization of a novel series of 2,5-diarylnicotinamides as potent and orally bioavailable orexin-2 receptor selective antagonists is described. A compound from this series demonstrated potent sleep promotion when dosed orally to EEG telemetrized rats.
Assuntos
Ácidos Nicotínicos/química , Ácidos Nicotínicos/farmacologia , Antagonistas dos Receptores de Orexina , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Ácidos Nicotínicos/síntese química , Ácidos Nicotínicos/farmacocinética , Receptores de Orexina/metabolismo , Ligação Proteica/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
RATIONALE: Previous studies have shown that activation of brain neuropeptide S receptor (NPSR) facilitates reinstatement of cocaine seeking elicited by environmental cues predictive of drug availability. This finding suggests the possibility that blockade of NPSR receptors may be of therapeutic benefit in cocaine addiction. To evaluate this hypothesis, we investigated the effect of two newly synthetized NPSR antagonists, namely the quinolinone-amide derivative NPSR-QA1 and the NPS peptidic analogue [D-Cys(tBu)5]NPS on cocaine self-administration and on discriminative cue-induced relapse to cocaine seeking in the rat. METHODS: Separate groups of rats self-administered food and cocaine 0.25 mg/kg/inf in FR1 and FR5 (fixed ratio reinforcement schedules) for 30-min and 2-h sessions per day. After food and cocaine intake reached baseline levels, the effect of NPSR-QA1 was tested on cocaine and food self-administration. The NPSR-QA1 was injected intraperitoneally and its effect on discriminative cue-induced reinstatement was evaluated, while [D-Cys(tBut)5]NPS was injected intracranially, intra-lateral hypothalamus, intra-perifornical area of the hypothalamus, and intra-central amygdala. The effect of the NPSR-QA1 on extinction of cocaine seeking was also assessed. RESULTS: Intraperitoneal administration of NPSR-QA1 (15-30 mg/kg) did not affect cocaine self-administration. Conversely, NPSR-QA1 (15-30 mg/kg) decreased discriminative cue-induced cocaine relapse. At the lowest dose, this effect was specific, while at the highest dose, NPSR-QA1 also reduced food self-administration. The efficacy of NPSR antagonism on cocaine seeking was confirmed with [D-Cys(tBu)5]NPS (10-30 nmol/rat) as it markedly inhibited relapse behavior following site-specific injection into the lateral hypothalamus and the perifornical area of the hypothalamus but not into the central amygdala. CONCLUSIONS: The identification of the NPS/NPSR system as an important new element involved in the physiopathology of cocaine addiction and the discovery of the anti-addictive properties of NPSR antagonists opens the possibility of exploring a new mechanism for cocaine addiction treatment.
Assuntos
Cocaína/farmacologia , Sinais (Psicologia) , Hipotálamo/metabolismo , Neuropeptídeos/antagonistas & inibidores , Receptores de Neuropeptídeos/efeitos dos fármacos , Amidas/farmacologia , Animais , Comportamento Aditivo/tratamento farmacológico , Relação Dose-Resposta a Droga , Comportamento de Procura de Droga/efeitos dos fármacos , Masculino , Neuropeptídeos/farmacologia , Quinolonas/farmacologia , Ratos , Ratos WistarRESUMO
The thalamic output during different behavioral states is strictly controlled by the firing modes of thalamocortical neurons. During sleep, their hyperpolarized membrane potential allows activation of the T-type calcium channels, promoting rhythmic high-frequency burst firing that reduces sensory information transfer. In contrast, in the waking state thalamic neurons mostly exhibit action potentials at low frequency (i.e., tonic firing), enabling the reliable transfer of incoming sensory inputs to cortex. Because of their nearly complete inactivation at the depolarized potentials that are experienced during the wake state, T-channels are not believed to modulate tonic action potential discharges. Here, we demonstrate using mice brain slices that activation of T-channels in thalamocortical neurons maintained in the depolarized/wake-like state is critical for the reliable expression of tonic firing, securing their excitability over changes in membrane potential that occur in the depolarized state. Our results establish a novel mechanism for the integration of sensory information by thalamocortical neurons and point to an unexpected role for T-channels in the early stage of information processing.
Assuntos
Potenciais de Ação/fisiologia , Canais de Cálcio Tipo T/fisiologia , Neocórtex/fisiologia , Neurônios/fisiologia , Tálamo/fisiologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Neurológicos , Neocórtex/citologia , Tálamo/citologia , Vigília/fisiologiaRESUMO
Thalamocortical (TC) neurons provide the major sensory input to the mammalian somatosensory cortex. Decreased activity of these cells may be pivotal in the ability of general anesthetics to induce loss of consciousness and promote sleep (hypnosis). T-type voltage-gated calcium currents (T-currents) have a key function regulating the cellular excitability of TC neurons and previous studies have indicated that volatile general anesthetics may alter the excitability of these neurons. Using a patch-clamp technique, we investigated the mechanisms whereby isoflurane, a common volatile anesthetic, modulates isolated T-currents and T-current-dependent excitability of native TC neurons in acute brain slices of the rat. In voltage-clamp experiments, we found that isoflurane strongly inhibited peak amplitude of T-current, yielding an IC(50) of 1.1 vol-% at physiological membrane potentials. Ensuing biophysical studies demonstrated that inhibition was more prominent at depolarized membrane potentials as evidenced by hyperpolarizing shifts in channel availability curves. In current-clamp experiments we found that isoflurane decreased the rate of depolarization of low-threshold-calcium spikes (LTCSs) and consequently increased the latency of rebound spike firing at the same concentrations that inhibited isolated T-currents. This effect was mimicked by a novel selective T-channel blocker 3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide (TTA-P2). In contrast, isoflurane and TTA-P2 had minimal effect on resting membrane potential and cell input resistance. We propose that the clinical properties of isoflurane may at least partly be provided by depression of thalamic T-currents.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/fisiologia , Córtex Cerebral/efeitos dos fármacos , Isoflurano/farmacologia , Neurônios/efeitos dos fármacos , Tálamo/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Cálcio/metabolismo , Córtex Cerebral/fisiologia , Relação Dose-Resposta a Droga , Feminino , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley , Tálamo/fisiologiaAssuntos
Indústria Farmacêutica/tendências , Biologia Molecular/tendências , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/genética , Neurofarmacologia/tendências , Pesquisa Translacional Biomédica/tendências , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/tendências , Indústria Farmacêutica/métodos , Humanos , Biologia Molecular/métodos , Neurofarmacologia/métodos , Pesquisa Translacional Biomédica/métodosRESUMO
STUDY OBJECTIVE: Sleep-wake traits are well-known to be under substantial genetic control, but the specific genes and gene networks underlying primary sleep-wake traits have largely eluded identification using conventional approaches, especially in mammals. Thus, the aim of this study was to use systems genetics and statistical approaches to uncover the genetic networks underlying 2 primary sleep traits in the mouse: 24-h duration of REM sleep and wake. DESIGN: Genome-wide RNA expression data from 3 tissues (anterior cortex, hypothalamus, thalamus/midbrain) were used in conjunction with high-density genotyping to identify candidate causal genes and networks mediating the effects of 2 QTL regulating the 24-h duration of REM sleep and one regulating the 24-h duration of wake. SETTING: Basic sleep research laboratory. PATIENTS OR PARTICIPANTS: Male [C57BL/6J × (BALB/cByJ × C57BL/6J*) F1] N(2) mice (n = 283). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: The genetic variation of a mouse N2 mapping cross was leveraged against sleep-state phenotypic variation as well as quantitative gene expression measurement in key brain regions using integrative genomics approaches to uncover multiple causal sleep-state regulatory genes, including several surprising novel candidates, which interact as components of networks that modulate REM sleep and wake. In particular, it was discovered that a core network module, consisting of 20 genes, involved in the regulation of REM sleep duration is conserved across the cortex, hypothalamus, and thalamus. A novel application of a formal causal inference test was also used to identify those genes directly regulating sleep via control of expression. CONCLUSION: Systems genetics approaches reveal novel candidate genes, complex networks and specific transcriptional regulators of REM sleep and wake duration in mammals.
Assuntos
Elementos Reguladores de Transcrição/genética , Sono REM/genética , Vigília/genética , Animais , Córtex Cerebral/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/genética , Genótipo , Hipotálamo/metabolismo , Masculino , Mesencéfalo/metabolismo , Camundongos , Camundongos Endogâmicos BALB C/genética , Camundongos Endogâmicos C57BL/genética , Locos de Características Quantitativas/genética , Tálamo/metabolismoRESUMO
Activity-dependent dendritic Ca(2+) signals play a critical role in multiple forms of nonlinear cellular output and plasticity. In thalamocortical neurons, despite the well established spatial separation of sensory and cortical inputs onto proximal and distal dendrites, respectively, little is known about the spatiotemporal dynamics of intrinsic dendritic Ca(2+) signaling during the different state-dependent firing patterns that are characteristic of these neurons. Here we demonstrate that T-type Ca(2+) channels are expressed throughout the entire dendritic tree of rat thalamocortical neurons and that they mediate regenerative propagation of low threshold spikes, typical of, but not exclusive to, sleep states, resulting in global dendritic Ca(2+) influx. In contrast, actively backpropagating action potentials, typical of wakefulness, result in smaller Ca(2+) influxes that can temporally summate to produce dendritic Ca(2+) accumulations that are linearly related to firing frequency but spatially confined to proximal dendritic regions. Furthermore, dendritic Ca(2+) transients evoked by both action potentials and low-threshold spikes are shaped by Ca(2+) uptake by sarcoplasmic/endoplasmic reticulum Ca(2+) ATPases but do not rely on Ca(2+)-induced Ca(2+) release. Our data demonstrate that thalamocortical neurons are endowed with intrinsic dendritic Ca(2+) signaling properties that are spatially and temporally modified in a behavioral state-dependent manner and suggest that backpropagating action potentials faithfully inform proximal sensory but not distal corticothalamic synapses of neuronal output, whereas corticothalamic synapses only "detect" Ca(2+) signals associated with low-threshold spikes.
Assuntos
Potenciais de Ação/fisiologia , Sinalização do Cálcio/fisiologia , Córtex Cerebral/citologia , Córtex Cerebral/fisiologia , Dendritos/fisiologia , Vias Neurais/citologia , Tálamo/citologia , Tálamo/fisiologia , Animais , Animais Recém-Nascidos , Cálcio/metabolismo , ATPases Transportadoras de Cálcio/metabolismo , Retículo Endoplasmático/fisiologia , Feminino , Masculino , Vias Neurais/fisiologia , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Sono/fisiologia , Vigília/fisiologiaRESUMO
IMPORTANCE OF THE FIELD: The orexin neuropeptide system plays a central role in maintaining arousal and wakefulness. It has been demonstrated that small molecule antagonists to the orexin receptors promote sleep in preclinical species and in patients with insomnia. AREAS COVERED IN THIS REVIEW: This review provides a summary of published patent applications claiming novel orexin antagonists from 2006 to mid-2009, covering both selective and dual orexin receptor antagonists. WHAT THE READER WILL GAIN: Readers will gain an overview of orexin biology focusing on genetic and pharmacological validation of this target for treating sleep disorders. Additionally, this review discusses the importance of receptor subtype selectivity and the potential role of subtype selective and dual orexin antagonists in treating psychiatric illnesses beyond insomnia. This review identifies companies that are significant contributors to the patent literature claiming novel orexin receptor antagonists. TAKE HOME MESSAGE: The study of the orexin system has emerged as one of the key new fields of investigation in neuroscience. The demonstration of clinical proof-of-concept for the treatment of primary insomnia by Actelion in early 2007 has spurred significant interest in this field and competition has markedly increased since 2006.
Assuntos
Hipnóticos e Sedativos/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Animais , Sistemas de Liberação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Humanos , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/fisiopatologia , Receptores de Orexina , Patentes como Assunto , Distúrbios do Início e da Manutenção do Sono/fisiopatologiaRESUMO
Although it is well established that low-voltage-activated T-type Ca(2+) channels play a key role in many neurophysiological functions and pathological states, the lack of selective and potent antagonists has so far hampered a detailed analysis of the full impact these channels might have on single-cell and neuronal network excitability as well as on Ca(2+) homeostasis. Recently, a novel series of piperidine-based molecules has been shown to selectively block recombinant T-type but not high-voltage-activated (HVA) Ca(2+) channels and to affect a number of physiological and pathological T-type channel-dependent behaviors. Here we directly show that one of these compounds, 3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide (TTA-P2), exerts a specific, potent (IC(50) = 22 nm), and reversible inhibition of T-type Ca(2+) currents of thalamocortical and reticular thalamic neurons, without any action on HVA Ca(2+) currents, Na(+) currents, action potentials, and glutamatergic and GABAergic synaptic currents. Thus, under current-clamp conditions, the low-threshold Ca(2+) potential (LTCP)-dependent high-frequency burst firing of thalamic neurons is abolished by TTA-P2, whereas tonic firing remains unaltered. Using TTA-P2, we provide the first direct demonstration of the presence of a window component of Ca(2+) channels in neurons and its contribution to the resting membrane potential of thalamic neurons and to the Up state of their intrinsically generated slow (<1 Hz) oscillation. Moreover, we demonstrate that activation of only a small fraction of the T-type channel population is required to generate robust LTCPs, suggesting that LTCP-driven bursts of action potentials can be evoked at depolarized potentials where the vast majority of T-type channels are inactivated.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/fisiologia , Neurônios/fisiologia , Tálamo/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Gatos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/efeitos dos fármacos , Ratos , Ratos Wistar , Tálamo/efeitos dos fármacosRESUMO
The discovery of a novel series of potent and selective T-type calcium channel antagonists is reported. Initial optimization of high-throughput screening leads afforded a 1,4-substituted piperidine amide 6 with good potency and limited selectivity over hERG and L-type channels and other off-target activities. Further SAR on reducing the basicity of the piperidine and introducing polarity led to the discovery of 3-axial fluoropiperidine 30 with a significantly improved selectivity profile. Compound 30 showed good oral bioavailability and brain penetration across species. In a rat genetic model of absence epilepsy, compound 30 demonstrated a robust reduction in the number and duration of seizures at 33 nM plasma concentration, with no cardiovascular effects at up to 5.6 microM. Compound 30 also showed good efficacy in rodent models of essential tremor and Parkinson's disease. Compound 30 thus demonstrates a wide margin between CNS and peripheral effects and is a useful tool for probing the effects of T-type calcium channel inhibition.