RESUMO
Despite the broad implications of the cannabinoid type 2 receptor (CB2) in neuroinflammatory processes, a suitable CB2-targeted probe is currently lacking in clinical routine. In this work, we synthesized 15 fluorinated pyridine derivatives and tested their binding affinities toward CB2 and CB1. With a sub-nanomolar affinity (Ki for CB2) of 0.8 nM and a remarkable selectivity factor of >12,000 over CB1, RoSMA-18-d6 exhibited outstanding in vitro performance characteristics and was radiofluorinated with an average radiochemical yield of 10.6 ± 3.8% (n = 16) and molar activities ranging from 52 to 65 GBq/µmol (radiochemical purity > 99%). [18F]RoSMA-18-d6 showed exceptional CB2 attributes as demonstrated by in vitro autoradiography, ex vivo biodistribution, and positron emission tomography (PET). Further, [18F]RoSMA-18-d6 was used to detect CB2 upregulation on postmortem human ALS spinal cord tissues. Overall, these results suggest that [18F]RoSMA-18-d6 is a promising CB2 PET radioligand for clinical translation.
Assuntos
Piridinas/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Receptor CB2 de Canabinoide/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Radioisótopos de Flúor/química , Humanos , Ligantes , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Tomografia por Emissão de Pósitrons , Piridinas/síntese química , Piridinas/farmacocinética , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Ratos Wistar , Medula Espinal/diagnóstico por imagem , Baço/diagnóstico por imagem , Relação Estrutura-Atividade , Trítio/químicaRESUMO
With N-Boc-protected 4-(allylaminomethyl)-2(5H)furanones as starting materials, a photochemical approach is presented to give 3,9-diazatricyclo[5.3.0.0(1,5)]decanes as conformationally restricted bis-pyrrolidines. The products are orthogonally protected at the two nitrogen atoms and exhibit, depending on the substitution pattern at positions C5, C6, and C7, latent C2 symmetry. When the furanones had a phenyl group at the 3-position (X(3)), alternative photochemical pathways were observed.
Assuntos
4-Butirolactona/química , Compostos Policíclicos/química , Compostos Policíclicos/síntese química , Reação de Cicloadição , Estrutura Molecular , Fotoquímica , Pirrolidinas/química , EstereoisomerismoRESUMO
A series of amides bearing a variety of amidine head groups was investigated as BACE1 inhibitors with respect to inhibitory activity in a BACE1 enzyme as well as a cell-based assay. Determination of their basicity as well as their properties as substrates of P-glycoprotein revealed that a 2-amino-1,3-oxazine head group would be a suitable starting point for further development of brain penetrating compounds for potential Alzheimer's disease treatment.
Assuntos
Amidas/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores de Proteases/química , Doença de Alzheimer/tratamento farmacológico , Amidas/metabolismo , Amidas/uso terapêutico , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Sítios de Ligação , Humanos , Simulação de Acoplamento Molecular , Inibidores de Proteases/metabolismo , Inibidores de Proteases/uso terapêutico , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-AtividadeRESUMO
An extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the pKa and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF3 substituted oxazine 89, a potent and highly brain penetrant BACE1 inhibitor, was able to reduce significantly CSF Aß40 and 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of Aß40 and 42 even after 24 h. In contrast to 89, compound 1b lacking the CF3 group was virtually inactive in vivo.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Animais , Química Encefálica , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Feminino , Flúor/química , Humanos , Indicadores e Reagentes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Moleculares , Oxazinas/síntese química , Oxazinas/farmacologia , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Difração de Raios XRESUMO
Intramolecular [2+2] photocycloaddition reactions of diversely substituted N-Boc protected 4-(allylaminomethyl)-2(5H)-furanones resulted in rigid products (53-75%) with three spatially defined positions for further functionalisation.
Assuntos
Pirrolidinas/química , Aminas/química , Compostos Azabicíclicos/química , Reação de Cicloadição , Furanos/química , Heptanos/química , Processos Fotoquímicos , EstereoisomerismoRESUMO
This study completes a series of papers devoted to the characterization of the non-competitive mGluR2/3 antagonist properties of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives with particular emphasis on derivatizations compatible with brain penetration and in vivo activity. Especially the compounds bearing a para-pyridine consistently showed in vivo activity in rat behavioral models after oral administration, for example, blockade of the mGluR2/3 agonist LY354740-induced hypoactivity and improvement of a working memory deficit induced either by LY354740 or scopolamine in the delayed match to position task (DMTP). Moreover, combination studies with a cholinesterase inhibitor show apparent synergistic effects on working memory impairment induced by scopolamine.
Assuntos
Azepinas/síntese química , Azepinas/farmacologia , Benzodiazepinonas/síntese química , Benzodiazepinonas/farmacologia , Antagonistas de Aminoácidos Excitatórios/síntese química , Transtornos da Memória/tratamento farmacológico , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Administração Oral , Animais , Azepinas/química , Comportamento Animal , Benzodiazepinonas/química , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Compostos Bicíclicos com Pontes/farmacologia , Inibidores da Colinesterase/farmacologia , Sinergismo Farmacológico , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Transtornos da Memória/induzido quimicamente , Ratos , Escopolamina/farmacologiaRESUMO
Binding of the mGlu2/3 antagonist HYDIA in the closed conformation model of mGlu2 causes repulsive interactions with Y216 in lobe II of the binding pocket, preventing closure of the VFT.Modulation of metabotropic glutamate 2/3 receptors represents a promising target for the treatment of neuropsychiatric disorders such as schizophrenia and depression. The novel mGlu2/3 ligand HYDIA ((1S,2R,3R,5R,6S)-2-amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid) is a conformationally restricted and hydroxylated glutamate analogue. HYDIA is a potent and selective competitive antagonist of L-glutamate at the mGlu2/3 receptors in spite of being structurally very similar to the bicyclic LY354740, which is a potent and selective mGlu2/3 agonist. By comparing these two ligands, this study delineate the interaction mode of (3)H-HYDIA at the mGlu2 receptor, using both mutagenesis studies and computational modeling. Binding of HYDIA in the closed conformation model of mGlu2 results in repulsive interaction with the Y216 residue, preventing closure of the binding pocket and thus receptor activation. Consequently, HYDIA is proposed to bind in an open conformation model of mGlu2. Mutation of the structurally important Y216 residue in the binding site caused complete loss of affinity of both (3)H-LY354740 and (3)H-HYDIA. T168 in lobe I was shown to have an important role in HYDIA binding, and in the open conformation model this residue is interacting with the amino group of HYDIA. The Y144 residue in lobe I is shown to be engaged in both receptor interlobe binding and ligand interaction. Receptor mutations at this position (Y144G, Y144S and Y144A) showed dramatic impact on binding affinity and functional effect of HYDIA. The mGlu2 receptor mutants with increased structural flexibility at this position, which is crucial for pocket closure, were clearly preferred. These studies highlight the unique properties of the novel (3)H-HYDIA ligand and provide further support to our understanding of binding and signal transduction mechanisms of the mGlu2 receptor.
Assuntos
Compostos Bicíclicos com Pontes/química , Modelos Moleculares , Receptores de Glutamato Metabotrópico/química , Substituição de Aminoácidos , Sítios de Ligação , Compostos Bicíclicos com Pontes/farmacologia , Linhagem Celular , Ácidos Dicarboxílicos/química , Ácidos Dicarboxílicos/farmacologia , Humanos , Mutagênese Sítio-Dirigida , Proteínas Mutantes/antagonistas & inibidores , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Ligação Proteica , Conformação Proteica , Estrutura Terciária de Proteína , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Receptores de Glutamato Metabotrópico/genética , Trítio/químicaRESUMO
A series of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives was evaluated as non-competitive mGluR2/3 antagonists. Replacement of the (2-aryl)-ethynyl-moiety in 8-position with smaller less lipophilic substituents produced compounds inhibiting the binding of [3H]-LY354740 to rat mGluR2 with low nanomolar affinity and consistent functional effect at both mGluR2 and mGluR3. These compounds were able to reverse LY354740-mediated inhibition of field excitatory postsynaptic potentials in the rat dentate gyrus and in vivo activity could be demonstrated by reversal of the LY354740-induced hypoactivity in mice after oral administration.
Assuntos
Benzodiazepinas/síntese química , Benzodiazepinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Benzodiazepinas/química , Células CHO , Cricetinae , Cricetulus , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Ratos , Receptores de Glutamato Metabotrópico/genética , Relação Estrutura-AtividadeRESUMO
The s-BuLi-sparteine base combination deprotonated the C-2' position of 1,2,3,4,5-pentamethylazaferrocene and subsequent reaction with a range of electrophiles gave C-2 substituted products in 76-93% yield and approximately 80% ee. The products could be recrystallised to enrich ee's to >90%. Resubjection of the initial addition products ( approximately 80% ee) to the deprotonation conditions led to a kinetic resolution to give products with >90% ee and superior overall yields compared to recrystallisation for the cases where the electrophiles were Ph2CO, MeI and Ph2S2. Transmetallation of the 2-lithiopentamethylazaferrocene ( approximately 80% ee) with ZnCl2 allowed palladium catalysed cross coupling with a variety of C-2 haloaryl, heteroaryl and vinyl groups to give some novel C-2' substituted pentamethylazaferrocene derivatives in 61-77% yield in 80% ee. Potential N,N-chelate ligands were recrystallised to >95% ee. A novel C2-symmetric bis-pentamethylazaferrocene could be synthesised by an iron catalysed oxidative coupling of the enatioenriched C-2 lithio derivative and in the presence of a PhMe-Et2O solvent mixture proceeded in 97% ee.
Assuntos
Compostos Ferrosos/química , Lítio/química , Compostos Organometálicos/química , Esparteína/química , Catálise , Compostos Ferrosos/síntese química , Ligantes , Conformação Molecular , Compostos Organometálicos/síntese química , EstereoisomerismoRESUMO
The asymmetric synthesis and receptor pharmacology of (1S,2R,3R,5R,6S)-2-amino-3-Hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (+)-9 (HYDIA) and a few of its O-alkylated derivatives are described. The key step of the synthesis utilizes Sharpless' asymmetric dihydroxylation (AD-beta) for the kinetic resolution of a bicyclic racemic precursor olefin. In contrast to the bicyclic glutamate analogue LY354740, which is a potent and selective agonist for the group II metabotropic glutamate receptors (mGluRs), these new conformationally restricted and also hydroxylated or alkoxylated glutamate analogues are potent and selective antagonists for the group II mGluRs.
Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Receptores de Glutamato Metabotrópico/agonistas , Alquilação , Animais , Ligação Competitiva , Compostos Bicíclicos com Pontes/síntese química , Agonistas de Aminoácidos Excitatórios/síntese química , Ácido Glutâmico/química , Ácido Glutâmico/farmacologia , Hidroxilação , Ligantes , Camundongos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives was evaluated as non-competitive mGluR2/3 antagonists. Replacement of a cyano group by a five-membered heterocycle produced compounds inhibiting the binding of [(3)H]-LY354740 to rat mGluR2 with low nanomolar affinity and consistent functional effect at both mGluR2 and mGluR3. Further modification to improve the physicochemical properties led eventually to compounds with the ability to reverse LY354740-mediated inhibition of field excitatory postsynaptic potentials in the rat dentate gyrus.
Assuntos
Azepinas/síntese química , Azepinas/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Azepinas/química , Células CHO , Cricetinae , Cricetulus , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
A series of 1,3-dihydrobenzo[b][1,4]diazepin-2-one derivatives was evaluated as non-competitive mGluR2/3 antagonists. Attachment of an 8-(2-aryl)-ethynyl-moiety produced compounds inhibiting the binding of [(3)H]-LY354740 to rat mGluR2 with low nanomolar affinity and consistent functional effect at both mGluR2 and mGluR3.