RESUMO
The Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) is a brain-relevant kinase involved in long-term potentiation and synaptic plasticity. We have recently pinpointed the CaMKIIα hub domain as the long-sought-after high-affinity target of γ-hydroxybutyrate ligands substantiated with a high-resolution cocrystal of 5-hydroxydiclofenac (3). Herein, we employed in silico approaches to rationalize and guide the synthesis and pharmacological characterization of a new series of analogues circumventing chemical stability problems associated with 3. The oxygen-bridged analogue 4d showed mid-nanomolar affinity and notable ligand-induced stabilization effects toward the CaMKIIα hub oligomer. Importantly, 4d displayed superior chemical and metabolic stability over 3 by showing excellent chemical stability in phosphate-buffered saline and high resistance to form reactive intermediates and subsequent sulfur conjugates. Altogether, our study highlights 4d as a new CaMKIIα hub high-affinity ligand with enhanced pharmacokinetic properties, representing a powerful tool compound for allosteric regulation of kinase activity with subtype specificity.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Diclofenaco , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Diclofenaco/análogos & derivados , Ligantes , Potenciação de Longa DuraçãoRESUMO
Herein we describe the synthesis and evaluation of antidepressant properties of seven analogues (1-7) of the low affinity/high capacity transporter blocker decynium-22 (D-22). All analogues (1-7) were synthesized via base promoted coupling reactions between N-alkylated-2-methylquinolinium iodides or N-alkylated-4-methylquinolinium iodides and electrophilic N-alkylated-2-iodoquinolinium iodides. All final compounds were purified by re-crystallization or preparative HPLC and initial evaluation studies included; 1) screening for in vitro α1-adrenoceptor activity (a property that can lead to unwanted side-effects), 2) measuring antidepressant-like activity in a mouse tail suspension test (TST), and 3) measuring effects upon mouse locomotion. The results showed some analogues have lower affinities at α1-adrenoceptors compared to D-22 and showed antidepressant-like activity without the need for co-administration of SSRIs. Additionally, many analogues did not affect mouse locomotion to the same extent as D-22. Plans for additional evaluations of these promising analogues, including measurement of antidepressant-like activity with co-administration of selective serotonin re-uptake inhibitors (SSRIs), are outlined.
Assuntos
Antidepressivos/farmacologia , Locomoção/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Quinolinas/farmacologia , Animais , Antidepressivos/síntese química , Antidepressivos/química , Relação Dose-Resposta a Droga , Camundongos , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-AtividadeRESUMO
The ρ-containing γ-aminobutyric acid typeâ A receptors (GABAA Rs) play an important role in controlling visual signaling. Therefore, ligands that selectively target these GABAA Rs are of interest. In this study, we demonstrate that the partial GABAA R agonist imidazole-4-acetic acid (IAA) is able to penetrate the blood-brain barrier inâ vivo; we prepared a series of α- and N-alkylated, as well as bicyclic analogues of IAA to explore the structure-activity relationship of this scaffold focusing on the acetic acid side chain of IAA. The compounds were prepared via IAA from l-histidine by an efficient minimal-step synthesis, and their pharmacological properties were characterized at native rat GABAA Rs in a [3 H]muscimol binding assay and at recombinant human α1 ß2 γ2S and ρ1 â GABAA Rs using the FLIPR™ membrane potential assay. The (+)-α-methyl- and α-cyclopropyl-substituted IAA analogues ((+)-6 a and 6 c, respectively) were identified as fairly potent antagonists of the ρ1 â GABAA R that also displayed significant selectivity for this receptor over the α1 ß2 γ2S GABAA R. Both 6 a and 6 c were shown to inhibit GABA-induced relaxation of retinal arterioles from porcine eyes.
Assuntos
Descoberta de Drogas , Imidazóis/farmacologia , Receptores de GABA-A/metabolismo , Vasos Retinianos/efeitos dos fármacos , Animais , Arteríolas/efeitos dos fármacos , Arteríolas/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Olho/efeitos dos fármacos , Humanos , Imidazóis/administração & dosagem , Imidazóis/química , Camundongos , Estrutura Molecular , Vasos Retinianos/metabolismo , Relação Estrutura-Atividade , SuínosRESUMO
In the title compound, C(13)H(7)ClN(4), the imidazopyridazine ring system is essentially planar [maximum deviation 0.015â (1)â Å]. It is inclined to the benzene ring of the benzonitrile group by 11.31â (2)°. In the crystal, molecules are linked via C-Hâ¯Cl and C-Hâ¯N interactions.
RESUMO
The inhibitory neurotransmitter, GABA, is a low-molecular-weight molecule that can achieve many low-energy conformations, which are recognized by GABA receptors and transporters. In this article, we assess the structure-activity relationship profiles of GABA analogs at the ionotropic ρ GABA(C) receptor. Such studies have significantly contributed to the design and development of potent and selective agonists and antagonists for this subclass of GABA receptors. With these tools in hand, the role of ρ GABA(C) receptors is slowly being realized. Of particular interest is the development of selective phosphinic acid analogs of GABA and their potential use in sleep disorders, inhibiting the development of myopia, and in improving learning and memory.
Assuntos
Química Farmacêutica , Receptores de GABA/química , Receptores de GABA/metabolismo , Ácido gama-Aminobutírico/análogos & derivados , Animais , Desenho de Fármacos , Agonistas GABAérgicos/química , Antagonistas GABAérgicos/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Ácido gama-Aminobutírico/metabolismoRESUMO
A series of bis(pyridinium)alkanes have been prepared and their antifungal activity, haemolytic activity and ability to inhibit fungal phospholipase B1 have been investigated, together with those of the commercially available antiseptics octenidine and dequalinium. Removal of the amino substituents from the pyridinium rings resulted in a significant decrease in antifungal activity. However, shortening or removing the alkyl chains attached to the amino groups had little effect on antifungal activity and significantly reduced haemolytic activity. Only octenidine was a strong inhibitor of fungal phospholipase B1.
Assuntos
Alcanos/síntese química , Alcanos/farmacologia , Antifúngicos/síntese química , Antifúngicos/farmacologia , Hemolíticos/síntese química , Hemolíticos/farmacologia , Compostos de Piridínio/síntese química , Compostos de Piridínio/farmacologia , Anfotericina B/farmacologia , Anti-Infecciosos Locais/farmacologia , Candida albicans/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Dequalínio/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Fungos/efeitos dos fármacos , Fungos/enzimologia , Humanos , Iminas , Técnicas In Vitro , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Micoses/microbiologia , Fosfolipases/antagonistas & inibidores , Piridinas/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of bisquaternary ammonium salts with a 12-carbon spacer between the positive charges were synthesized, and their antifungal activity has been investigated. Compounds with butyl, pentyl, and isopentyl headgroups were the most potent antifungal agents with MICs in the range of 2.2-5.5 microM against both Cryptococcus neoformans and Candida albicans. The antifungal activity of these compounds correlated with their inhibition of cryptococcal phospholipase B1 (PLB1), a newly identified virulence factor. This indicates that the mode of action of these compounds may be inhibition of the fungal PLB1 enzyme, further validating this enzyme as a target for the development of novel antifungal therapies.