RESUMO
Mutations in the MBOAT7 gene have been described in 43 patients, belonging to 18 families, showing nonspecific clinical features (intellectual disability [ID], seizures, microcephaly or macrocephaly, and mild to moderate cerebellar atrophy) that make the clinical diagnosis difficult. Here we report the first Italian patient, a 22.5-year-old female, one of the oldest reported, born to apparently consanguineous parents. She shows severe ID, macrocephaly, seizures, aggressive outbursts, hyperphagia. We also documented progressive atrophy of the cerebellar vermis, that appeared not before the age of 7. The whole-exome sequencing of the trio identified a novel homozygous variant c.1057_1058delGCinsCA (p.Ala353His) in the MBOAT7 gene. The variant is considered to be likely pathogenic, since it is absent from population database and it lies in a highly conserved amino acid residue. This disorder has a neurometabolic pathogenesis, implicating a phospholipid remodeling abnormalities. A brain hydrogen-magnetic resonance spectroscopy (H-MRS) examination in our patient disclosed a peculiar neurometabolic profile in the cerebellar hemispheric region. This new finding could address the clinical suspicion of MBOAT7-related disorder, among the wide range of genetic conditions associated with ID and cerebellar atrophy. Moreover, the documented progression of cerebellar atrophy and the worsening of the disease only after some years open to the possibility of a therapeutic window after birth.
Assuntos
Aciltransferases/genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Atrofias Olivopontocerebelares/genética , Adolescente , Adulto , Cerebelo/diagnóstico por imagem , Criança , Consanguinidade , Exoma/genética , Feminino , Homozigoto , Humanos , Deficiência Intelectual/patologia , Masculino , Atrofias Olivopontocerebelares/patologia , Linhagem , Sequenciamento do Exoma , Adulto JovemRESUMO
During the lead optimization of NK(1)/NK(3) receptor antagonists program, a focused exploration of molecules bearing a lactam moiety was performed. The aim of the investigation was to identify the optimal position of the carbonyl and hydroxy methyl group in the lactam moiety, in order to maximize the in vitro affinity and the level of insurmountable antagonism at both NK(1) and NK(3) receptors. The synthesis and biological evaluation of these novel lactam derivatives, with potent and balanced NK(1)/NK(3) activity, were reported in this paper.
Assuntos
Antipsicóticos/química , Antipsicóticos/farmacologia , Lactamas/química , Lactamas/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Receptores da Neurocinina-3/antagonistas & inibidores , Esquizofrenia/tratamento farmacológico , Humanos , Modelos Moleculares , Receptores da Neurocinina-1/metabolismo , Receptores da Neurocinina-3/metabolismo , Relação Estrutura-AtividadeRESUMO
This article deals with the synthesis and the activities of some 1,5-dialkyl-3-arylureido-1,5-benzodiazepin-2,4-diones which were prepared as potential CCK2 antagonists, with the intention to find a possible follow up of our lead compound GV150013, showing an improved pharmacokinetic profile. The phenyl ring at N-5 was replaced with more hydrophilic substituents, like alkyl groups bearing basic functions. In some cases, the resolution of the racemic key intermediates 3-amino-benzodiazepines was also accomplished. Among the compounds synthesized and characterised so far in this class, the 5-morpholinoethyl derivative 54, was selected as potential follow up of GV150013 and submitted for further evaluation.
Assuntos
Benzodiazepinonas/farmacologia , Receptor de Colecistocinina B/antagonistas & inibidores , Animais , Benzodiazepinonas/síntese química , Benzodiazepinonas/química , Cães , Cobaias , Camundongos , Estrutura Molecular , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
The synthesis and the SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The new scaffolds of the [g]-fused and the hetero-fused tricyclic benzazepine are here reported together with their pharmacokinetic profile.
Assuntos
Benzazepinas/síntese química , Benzazepinas/farmacologia , Antagonistas de Dopamina/síntese química , Antagonistas de Dopamina/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Benzazepinas/química , Técnicas de Química Combinatória , Antagonistas de Dopamina/química , Desenho de Fármacos , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
The synthesis and SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The introduction of a tricyclic [h]-fused benzazepine moiety on the recently disclosed scaffold of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines is reported. A full rat pharmacokinetic characterization is also reported.
Assuntos
Benzazepinas/síntese química , Benzazepinas/farmacologia , Antagonistas de Dopamina/síntese química , Antagonistas de Dopamina/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Benzazepinas/química , Técnicas de Química Combinatória , Antagonistas de Dopamina/química , Desenho de Fármacos , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
The discovery of new highly potent and selective dopamine D3 receptor antagonists has recently permitted characterization of the role of the dopamine D3 receptor in a wide range of preclinical animal models. A novel series of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines demonstrating a high level of D3 affinity and selectivity with an excellent pharmacokinetic profile is reported here. In particular, the pyrazolyl derivative 35 showed good oral bioavailability and brain penetration associated with high potency and selectivity in vitro. In vivo characterization of 35 confirmed that this compound blocks the expression of nicotine- and cocaine-conditioned place preference in the rat, prevents nicotine-triggered reinstatement of nicotine-seeking behavior in the rat, reduces oral operant alcohol self-administration in the mouse, increases extracellular levels of acetylcholine in the rat medial prefrontal cortex, and potentiates the amplitude of the relative cerebral blood volume response to d-amphetamine in a regionally specific manner in the rat brain.
Assuntos
Benzazepinas/síntese química , Receptores de Dopamina D3/antagonistas & inibidores , Triazóis/síntese química , Acetilcolina/metabolismo , Administração Oral , Consumo de Bebidas Alcoólicas/prevenção & controle , Animais , Benzazepinas/farmacocinética , Benzazepinas/farmacologia , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Cobaias , Antagonistas dos Receptores Histamínicos H1/síntese química , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D3/agonistas , Receptores Histamínicos H1/metabolismo , Relação Estrutura-Atividade , Tabagismo/prevenção & controle , Triazóis/farmacocinética , Triazóis/farmacologiaRESUMO
Docking is a computational technique that samples conformations of small molecules in protein binding sites; scoring functions are used to assess which of these conformations best complements the protein binding site. An evaluation of 10 docking programs and 37 scoring functions was conducted against eight proteins of seven protein types for three tasks: binding mode prediction, virtual screening for lead identification, and rank-ordering by affinity for lead optimization. All of the docking programs were able to generate ligand conformations similar to crystallographically determined protein/ligand complex structures for at least one of the targets. However, scoring functions were less successful at distinguishing the crystallographic conformation from the set of docked poses. Docking programs identified active compounds from a pharmaceutically relevant pool of decoy compounds; however, no single program performed well for all of the targets. For prediction of compound affinity, none of the docking programs or scoring functions made a useful prediction of ligand binding affinity.
Assuntos
Ligantes , Proteínas/química , Relação Quantitativa Estrutura-Atividade , Algoritmos , Sítios de Ligação , Desenho de Fármacos , Modelos Moleculares , Conformação Molecular , Ligação Proteica , SoftwareRESUMO
Herein we report a detailed description of the structure-activity relationships for a novel series of "C-linked" 1,2,4-triazolylazabicyclo[3.1.0]hexanes. These derivatives are endowed with very high in vitro affinity and selectivity for the dopamine D(3) receptor. An optimization with respect to undesired affinity toward the hERG potassium channel is also reported. Members of this compound series also show excellent in vitro and in vivo pharmacokinetic properties.
Assuntos
Compostos Aza/química , Compostos Bicíclicos com Pontes/química , Hexanos/química , Receptores de Dopamina D3/antagonistas & inibidores , Triazóis/química , Animais , Sítios de Ligação , Simulação por Computador , Hexanos/síntese química , Hexanos/farmacocinética , Humanos , Ratos , Receptores de Dopamina D3/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes with high affinity and selectivity for the DA D(3) receptor and excellent pharmacokinetic profiles was recently reported. We also recently discussed the role of the linker associated with the triazole moiety. In this manuscript, we are reporting a detailed exploration of the region of the receptor interacting with the amine terminus of the scaffold wherein SAR and developability data associated with these novel templates was undertaken.
Assuntos
Compostos Azabicíclicos/síntese química , Modelos Moleculares , Receptores de Dopamina D3/antagonistas & inibidores , Triazóis/síntese química , Animais , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Células CHO , Domínio Catalítico , Cricetinae , Cricetulus , Humanos , Técnicas In Vitro , Microssomos Hepáticos/metabolismo , Ensaio Radioligante , Ratos , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologiaRESUMO
The discovery of new highly potent and selective dopamine (DA) D(3) receptor antagonists has recently allowed the characterization of the DA D(3) receptor in a range of preclinical animal models of drug addiction. A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes, members of which showed a high affinity and selectivity for the DA D(3) receptor and excellent pharmacokinetic profiles, is reported here. Members of a group of derivatives from this series showed good oral bioavailability and brain penetration and very high in vitro affinity and selectivity for the DA D(3) receptor, as well as high in vitro potency for antagonism at this receptor. Several members of this series also significantly attenuate the expression of conditioned place preference (CPP) to nicotine and cocaine.
Assuntos
Hexanos/química , Hexanos/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Simulação por Computador , Desenho de Fármacos , Cobaias , Humanos , Masculino , Modelos Animais , Modelos Químicos , Estrutura Molecular , Receptores de Dopamina D3/biossíntese , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A pharmacophore model for triple reuptake inhibitors and the new class of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes were recently reported. Further investigation in this area led to the identification of a new series of potent and selective triple reuptake inhibitors endowed with good developability characteristics. Excellent bioavailability and brain penetration are associated with this series of 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanes together with high in vitro potency and selectivity at SERT, NET, and DAT. In vivo microdialysis experiments in different animal models and receptor occupancy studies in rat confirmed that derivative 17 showed an appropriate profile to guarantee further progression of the compound.
Assuntos
Transtorno Depressivo/tratamento farmacológico , Heptanos/química , Heptanos/farmacologia , Inibidores da Captação de Neurotransmissores/química , Inibidores da Captação de Neurotransmissores/farmacologia , Animais , Antidepressivos/síntese química , Antidepressivos/química , Antidepressivos/farmacologia , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Encéfalo/metabolismo , Transtorno Depressivo/metabolismo , Dopamina/metabolismo , Heptanos/síntese química , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Camundongos , Microdiálise , Modelos Moleculares , Inibidores da Captação de Neurotransmissores/síntese química , Norepinefrina/metabolismo , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Relação Estrutura-AtividadeRESUMO
The discovery of new highly potent and selective triple reuptake inhibitors is reported. The new classes of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes are described together with detailed SAR. Appropriate decoration of the scaffolds was achieved with the help of a triple reuptake inhibitor pharmacophore model detailed here. Selected derivatives showed good oral bioavailability (>30%) and brain penetration (B/B > 4) in rats associated with high in vitro potency and selectivity at SERT, NET, and DAT. Among these compounds, microdialysis and in vivo experiments confirm that derivative 15 has an appropriate developability profile to be considered for further progression.
Assuntos
Compostos Azabicíclicos/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Animais , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacocinética , Ligação Competitiva , Monoaminas Biogênicas/metabolismo , Disponibilidade Biológica , Transporte Biológico/efeitos dos fármacos , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Humanos , Masculino , Camundongos , Microdiálise , Microssomos Hepáticos/metabolismo , Modelos Químicos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Córtex Pré-Frontal/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
Design, synthesis and properties of a new tricyclic series of selective 5-HT2C receptor antagonists are reported. Conformational analysis of a 2-phenyl-dihydropyrrolone scaffold suggested that ring fusion, locking coplanarity between the rings of this moiety, might be tolerated by the 5-HT2C receptor. An interesting effect of this is the change of the nature of the carbon-carbon double bond of the lactam ring from vinylic to aromatic. The changes were found to result in a favourable profile at both, receptor and in vivo level.
Assuntos
Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Alquilação , Animais , Disponibilidade Biológica , Desenho de Fármacos , Compostos Heterocíclicos/farmacocinética , Humanos , Indicadores e Reagentes , Masculino , Modelos Moleculares , Conformação Molecular , Ratos , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptor 5-HT2B de Serotonina/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Two independent approaches resulted in the identification of a series of isoindolone derivatives as potent and selective 5-HT2C antagonists. From a Medicinal Chemistry perspective this template was considered interesting as it allowed the incorporation of the carbon-carbon double bond of an earlier dihydropyrrolone series in an aromatic system within a comparatively simple and compact motif. Additionally an in silico screening approach of the corporate database using a 5-HT2C pharmacophore model resulted in the identification of a related structure containing this template. The strategy used to optimise potency at the target receptor and to improve the pharmacokinetic profile is described, resulting in molecules combining high potency with good selectivity and oral bioavailability.
Assuntos
Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Indóis/síntese química , Indóis/farmacologia , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacologia , Animais , Disponibilidade Biológica , Bases de Dados Factuais , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Isoindóis , Masculino , Ratos , Relação Estrutura-AtividadeRESUMO
A "data mining" methodology based on substructural analysis and standard 1024 Daylight fingerprints as descriptors was applied to a set of known antagonists of a subfamily of ligand-gated ion channels comprising nicotinic acetylcholine receptors (nAChR's), 5-hydroxytryptamine, gamma-amino butyric acid-A, and glycine receptors. The derived scoring function was used to generate a focused set that was screened for alpha7 nAChR, resulting in the identification of novel alpha7 ligands easily amenable to chemical modification. Finally, the same scoring function was applied retrospectively to other in-house sets screened for the same target in the same assay. The results and performance of the method are described in detail.
Assuntos
Desenho de Fármacos , Ativação do Canal Iônico , Ligantes , Modelos Químicos , Receptores Nicotínicos/química , Algoritmos , Preparações Farmacêuticas/químicaRESUMO
Within the continuous quest for the discovery of novel compounds able to treat anxiety and depression, the generation of a pharmacophore model for 5-HT2C receptor antagonists and the discovery of a new class of potent and selective 5-HT2C molecules are reported.