RESUMO
Antipsychotic medications function by blocking postsynaptic dopaminergic signaling in the central nervous system. Dopamine transmission can also be modulated presynaptically by inhibitors of vesicular monoamine transporter 2 (VMAT2), which inhibit loading of dopamine into presynaptic vesicles. Here we investigated the combination of these mechanisms in animal models of schizophrenia and weight gain (a primary side effect of antipsychotics). When dosed alone, the highly selective VMAT2 inhibitor RRR-dihydrotetrabenazine (RRR-DHTBZ, also known as [+]-α-HTBZ) elicited efficacy comparable to conventional antipsychotics in prepulse inhibition and conditioned avoidance models without eliciting weight gain. In combination experiments, synergy was observed: subthreshold doses of RRR-DHTBZ and risperidone or olanzapine produced robust efficacy, and in dose response experiments, RRR-DHTBZ increased the antipsychotic potency in the efficacy models but did not affect weight gain. The combinations did not affect plasma compound concentrations. The synergy is consistent with VMAT2 inhibition blocking the counterproductive presynaptic stimulation of dopamine by antipsychotics. These results suggest a therapeutic strategy of adding a VMAT2 inhibitor to lower the antipsychotic dose and reduce the side effect burden of the antipsychotic while maintaining and potentially enhancing its therapeutic effects. SIGNIFICANCE STATEMENT: Antipsychotics are often necessary and life-changing medications that reduce psychotic symptoms; however, these benefits come with a high side effect burden. This study shows that combining these postsynaptic dopaminergic modulators with a presynaptic dopamine modulator (vesicular monoamine transporter 2 [VMAT2] inhibitor) potentiates efficacy synergistically in animal models of schizophrenia without potentiating weight gain. Our data suggest that adding a VMAT2 inhibitor may be a viable therapeutic strategy for reducing antipsychotic side effects by lowering antipsychotic dose while maintaining therapeutic efficacy.
Assuntos
Antipsicóticos , Esquizofrenia , Animais , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Dopamina , Modelos Animais , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Proteínas Vesiculares de Transporte de Monoamina , Aumento de PesoRESUMO
The application of kinetics to research and therapeutic development of G-protein-coupled receptors has become increasingly valuable. Pharmacological models provide the foundation of pharmacology, providing concepts and measurable parameters such as efficacy and potency that have underlain decades of successful drug discovery. Currently there are few pharmacological models that incorporate kinetic activity in such a way as to yield experimentally-accessible drug parameters. In this study, a kinetic model of pharmacological response was developed that provides a kinetic descriptor of efficacy (the transduction rate constant, kτ) and allows measurement of receptor-ligand binding kinetics from functional data. The model assumes: (1) receptor interacts with a precursor of the response ("Transduction potential") and converts it to the response. (2) The response can decay. Familiar response vs time plots emerge, depending on whether transduction potential is depleted and/or response decays. These are the straight line, the "association" exponential curve, and the rise-and-fall curve. Convenient, familiar methods are described for measuring the model parameters and files are provided for the curve-fitting program Prism (GraphPad Software) that can be used as a guide. The efficacy parameter kτ is straightforward to measure and accounts for receptor reserve; all that is required is measurement of response over time at a maximally-stimulating concentration of agonist. The modular nature of the model framework allows it to be extended. Here this is done to incorporate antagonist-receptor binding kinetics and slow agonist-receptor equilibration. In principle, the modular framework can incorporate other cellular processes, such as receptor desensitization. The kinetic response model described here can be applied to measure kinetic pharmacological parameters than can be used to advance the understanding of GPCR pharmacology and optimize new and improved therapeutics.
Assuntos
Descoberta de Drogas , Modelos Biológicos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Software , Animais , Humanos , CinéticaRESUMO
G-Protein coupled receptors (GPCRs) have been, and remain a key target of drug discovery programs for human disease. While many drugs have been developed that interact with these proteins in the simple classic manner - that is - physically blocking the cognate ligand from simply binding to its target receptor, drug discovery approaches have elucidated alternative more complex methods by which small molecules can interact with these receptors and block their function. This is most evident in the Class B GPCRs where the cognate ligands are relatively large peptides with multiple points of contact on the GPCR spanning both hydrophilic and hydrophobic domains on the same protein to elicit function. It has therefore been difficult to precisely determine not only the mechanism by which a small molecule can inhibit the function of a large peptide but also the nature of that mechanism that drives the differences in efficacy. This review will examine in detail the nature of small molecule inhibition of corticotropin-releasing factor receptors and illustrate the role that allosteric binding and kinetics play in the functional inhibition of this Class B GPCR.
Assuntos
Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Regulação Alostérica/efeitos dos fármacos , Animais , Ensaios Clínicos como Assunto , Descoberta de Drogas/métodos , Humanos , Cinética , Modelos Moleculares , Receptores de Hormônio Liberador da Corticotropina/química , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
The structure-activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1H-benzimidazoles are described. In the lead optimization process, the pK(a) and/or logP of benzimidazole analogs were reduced either by attachment of polar substituents to the piperidine nitrogen or incorporation of heteroatoms into the piperidine heterocycle. Compounds 9a and 9b in the morpholine series and 10g in the thiomorpholine series demonstrated improved selectivity and CNS profiles compared to lead compound 2 and these are potential candidates for evaluation as sedative hypnotics.
Assuntos
Benzimidazóis/síntese química , Antagonistas dos Receptores Histamínicos H1/farmacologia , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Benzimidazóis/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Desenho de Fármacos , Canal de Potássio ERG1 , Eletrofisiologia/métodos , Canais de Potássio Éter-A-Go-Go/química , Humanos , Hipnóticos e Sedativos/farmacologia , Concentração Inibidora 50 , Cinética , Microssomos Hepáticos/efeitos dos fármacos , Modelos Químicos , Morfolinas/química , Nitrogênio/química , Piperidinas/química , Receptores Histamínicos H1/química , Relação Estrutura-AtividadeRESUMO
Structure-activity relationship studies were conducted to reduce CYP2D6-mediated metabolism in a series of indene H(1)-antihistamines. Reductions in pK(a) via incorporation of a ß-fluoro substituent or a heteroaryl moiety were shown to reduce contributions to metabolism through this pathway. Several compounds, including 8l, 8o, and 12f were identified with promising primary in vitro profiles and reduced biotransformation via CYP2D6.
Assuntos
Citocromo P-450 CYP2D6/química , Antagonistas dos Receptores Histamínicos H1/química , Indenos/química , Pirazinas/química , Receptores Histamínicos H1/química , Biotransformação , Citocromo P-450 CYP2D6/metabolismo , Antagonistas dos Receptores Histamínicos H1/síntese química , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Indenos/síntese química , Indenos/farmacocinética , Pirazinas/síntese química , Pirazinas/farmacocinética , Receptores Histamínicos H1/metabolismo , Relação Estrutura-AtividadeRESUMO
Analogs of the known H(1)-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study.
Assuntos
Antagonistas dos Receptores Histamínicos H1/química , Indenos/química , Piridazinas/química , Receptores Histamínicos H1/química , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Animais , Citocromo P-450 CYP2D6/metabolismo , Dimetideno/química , Eletroencefalografia , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Indenos/farmacocinética , Indenos/uso terapêutico , Microssomos Hepáticos/metabolismo , Modelos Animais , Piridazinas/farmacocinética , Piridazinas/uso terapêutico , Ratos , Receptores Histamínicos H1/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of 2-(3-aminopiperidine)-benzimidazoles were identified as selective H(1)-antihistamines for evaluation as potential sedative hypnotics. Representative compounds showed improved hERG selectivity over a previously identified 2-aminobenzimidazole series. While hERG activity could be modulated via manipulation of the benzimidazole N1 substituent, this approach led to a reduction in CNS exposure for the more selective compounds. One example, 9q, retained a suitable selectivity profile with CNS exposure equivalent to known centrally active H(1)-antihistamines.
Assuntos
Benzimidazóis/química , Sistema Nervoso Central/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/química , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Benzimidazóis/síntese química , Benzimidazóis/uso terapêutico , Descoberta de Drogas , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Antagonistas dos Receptores Histamínicos H1/síntese química , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Relação Estrutura-AtividadeRESUMO
SAR of lead benzothiophene H(1)-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H(1)-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound.
Assuntos
Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Tiofenos/farmacologia , Tiofenos/farmacocinética , Antagonistas dos Receptores Histamínicos H1/química , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Receptores Histamínicos H1/metabolismo , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/uso terapêuticoRESUMO
A series of indene analogs of the H(1)-antihistamine (-)-R-dimethindene was evaluated for selectivity in the search for potentially improved sedative-hypnotics. Variation of the 6-substitutent in the indene core in combination with a pendant electron rich heterocycle led to the identification of several potent H(1)-antihistamines with desirable selectivity over CYP enzymes, the M(1) muscarinic receptor and the hERG channel. These compounds were candidates for further ADME profiling and in vivo evaluation.
Assuntos
Antagonistas dos Receptores Histamínicos/uso terapêutico , Indenos/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Indenos/química , Indenos/farmacologiaRESUMO
Analogues of the known H(1)-antihistamine R-dimethindene were profiled as potential agents for the treatment of insomnia. Several highly selective compounds were efficacious in rodent sleep models. On the basis of overall profile, indene 1d and benzothiophene 2a had pharmacokinetic properties suitable for evaluation in night time dosing. Compound 2a did not show an in vivo cardiovascular effect from weak hERG channel inhibition.
Assuntos
Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Animais , Encéfalo/metabolismo , Dimetideno/metabolismo , Dimetideno/farmacocinética , Dimetideno/farmacologia , Dimetideno/uso terapêutico , Eletroencefalografia/efeitos dos fármacos , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Antagonistas dos Receptores Histamínicos H1/metabolismo , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Humanos , Ratos , Receptores Muscarínicos/metabolismo , Sono/efeitos dos fármacos , Especificidade por SubstratoRESUMO
Beginning with the discovery of the structure of deoxyribose nucleic acid in 1953, by James Watson and Francis Crick, the sequencing of the entire human genome some 50 years later, has begun to quantify the classes and types of proteins that may have relevance to human disease with the promise of rapidly identifying compounds that can modulate these proteins so as to have a beneficial and therapeutic outcome. This so called 'drugable space' involves a variety of membrane-bound proteins including the superfamily of G-protein-coupled receptors (GPCRs), ion channels, and transporters among others. The recent number of novel therapeutics targeting membrane-bound extracellular proteins that have reached the market in the past 20 years however pales in magnitude when compared, during the same timeframe, to the advancements made in the technologies available to aid in the discovery of these novel therapeutics. This review will consider select examples of extracellular drugable targets and focus on the GPCRs and ion channels highlighting the corticotropin releasing factor (CRF) type 1 and gamma-aminobutyric acid receptors, and the Ca(V)2.2 voltage-gated ion channel. These examples will elaborate current technological advancements in drug discovery and provide a prospective framework for future drug development.