RESUMO
Since the 1950's, AMP-kinase (AMPK) has been used as a promising target for the development of antidiabetic drugs against Type 2 diabetes mellitus (T2D). Indeed, the canonical antidiabetic drug metformin recruits, at least partially, AMPK activation for its therapeutic effect. Herein we present design and synthesis of 20 novel relatively polar cyclic and acyclic dithioacetals of 2-(Het)arylchroman-6-carbaldehydes, 2-phenyl-1,4-benzodioxane-6-carbaldehyde, and 2-phenylbenzofuran-5-carbaldehyde, which were developed as potential AMPK activators. Three of the synthesized dithioacetals demonstrated significant enhancement (≥70%) of glucose uptake in rat L6 myotubes. Noteworthy, one of the dithioacetals, namely 4-(6-(1,3-dithian-2-yl)chroman-2-yl)pyridine, exhibited high potency comparing to other molecules. It increased the rate of glucose uptake in rat L6 myotubes and augmented insulin secretion from rat INS-1E cells in pharmacological relevant concentrations (up to 2 µM). Both effects were mediated by activation of AMPK. In addition, the compound showed excellent pharmacokinetic profile in healthy mice, including maximal oral bioavailability. Such bifunctionality (increased glucose uptake and insulin secretion) can be used as a starting point for the development of a novel class of antidiabetic drugs with dual activity that is relevant for T2D treatment.
Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemiantes , Ratos , Camundongos , Animais , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Proteínas Quinases Ativadas por AMP , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose/farmacologia , Linhagem Celular , Fibras Musculares Esqueléticas , Insulina/farmacologiaRESUMO
Innovative organogold(I) antibacterial compounds were synthesized by click chemistry with triethylphosphine-gold(I) azides and an alkyne derivative. The resulting organo-gold(I) compounds exhibit high levels of antibacterial activity against Gram-positive pathogens, with particularly low MICs against Clostridium difficile.
Assuntos
Antibacterianos/química , Compostos Organoáuricos/química , Fosfinas/química , Triazóis/química , Alcinos/química , Antibacterianos/farmacologia , Azidas/química , Catálise , Química Click , Clostridioides difficile , Reação de Cicloadição , Descoberta de Drogas , Resistência a Medicamentos , Enterococcus/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Compostos Organoáuricos/farmacologia , Fosfinas/farmacologia , Staphylococcus/efeitos dos fármacos , Triazóis/farmacologiaAssuntos
Ampicilina/análogos & derivados , Ampicilina/síntese química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Ouro/química , Bactérias Gram-Positivas/efeitos dos fármacos , Ampicilina/química , Ampicilina/farmacologia , Antibacterianos/química , Testes de Sensibilidade Microbiana , Estrutura MolecularRESUMO
Cyclic tetrapeptide c[Phe-pro-Phe-trp] 2, a diastereomer of CJ-15,208 (1), was identified as a potent dual kappa/mu opioid receptor antagonist devoid of delta opioid receptor affinity against cloned human receptors: K(i) (2)=3.8nM (kappa), 30nM (mu); IC(50) ([(35)S]GTPgammaS binding)=140nM (kappa), 21nM (mu). The d-tryptophan residue rendered 2 ca. eightfold and fourfold more potent at kappa and mu, respectively, than the corresponding l-configured tryptophan in the natural product 1. Phe analogs 3-10, designed to probe the effect of substituents on receptor affinity and selectivity, possessed K(i) values ranging from 14 to 220nM against the kappa opioid receptor with mu/kappa ratios of 0.45-3.0. An alanine scan of 2 yielded c[Ala-pro-Phe-trp] 12, an analog equipotent to 2. Agents 2 and 12 were pure antagonists in vitro devoid of agonist activity. Ac-pro-Phe-trp-Phe-NH(2)16 and Ac-Phe-trp-Phe-pro-NH(2)17 two of the eight possible acyclic peptides derived from 1 and 2, were selective, modestly potent mu ligands: K(i) (16)=340nM (mu); K(i) (17)=360nM (mu).
Assuntos
Peptídeos Cíclicos/química , Receptores Opioides kappa/antagonistas & inibidores , Simulação por Computador , Cristalografia por Raios X , Humanos , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacologia , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/antagonistas & inibidores , Receptores Opioides mu/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of opioid peptide ligands containing modified N-terminal tyrosine (Tyr) residues was prepared and evaluated against cloned human mu, delta, and kappa opioid receptors. This work extends the recent discovery that (S)-4-carboxamidophenylalanine (Cpa) is an effective tyrosine bioisostere. Amino acids containing negatively charged functional groups in place of tyrosine's phenolic hydroxyl lacked receptor affinity, while exchange of Tyr for (S)-4-aminophenylalanine was modestly successful. Peptides containing the new amino acids, (S)-4-carboxamido-2,6-dimethylphenylalanine (Cdp) and (S)-beta-(2-aminobenzo[d]thiazol-6-yl)alanine (Aba), displayed binding (K(i)) and functional (EC(50)) profiles comparable to the parent ligands at the three receptors. Cdp represents the best performing Tyr surrogate in terms of overall activity, while Cpa and Aba show a subtle proclivity toward the delta receptor.
Assuntos
Química Farmacêutica/métodos , Peptídeos/química , Receptores Opioides/química , Tirosina/química , Clonagem Molecular , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Cinética , Ligantes , Modelos Químicos , Conformação Molecular , Receptores Opioides delta/química , Receptores Opioides kappa/química , Receptores Opioides mu/químicaRESUMO
The series of trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines have been widely investigated as opioid receptor antagonists. One of our research goals was to explore the bioactive conformation of the N-phenethyl trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine derivative 3, prototypical mu-opioid antagonist in this series. In this effort, the rotational degrees of freedom of the N-substituent of 3 were limited by incorporation of an ethylene bridge between the piperidine 2- or 6-position of 3 and the benzylic position of the N-phenethyl moiety. The overall modification led to a novel series of fused bicyclic derivatives of the octahydroquinolizine chemical class, conformationally restricted analogue of 3. The constrained analogues 6 and 9 showed high affinity toward the mu-opioid receptor. Compound 6 was found to be a mu-opioid antagonist, whereas the constrained analogue 9 displayed potent mu-agonist activity in vitro. This study provides additional information about the molecular determinants for mu recognition, the structural features affecting ligand binding, and the structure function relationships.
Assuntos
Piperidinas/síntese química , Receptores Opioides mu/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Cricetulus , Cristalografia por Raios X , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Ligantes , Modelos Moleculares , Conformação Molecular , Piperidinas/química , Piperidinas/farmacologia , Ensaio Radioligante , Receptores Opioides mu/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Structure-activity relationships at the 2alpha-position of the piperidine ring of the trans-4,5-dimethyl-4-(3-hydroxyphenyl)piperidine mu-opioid antagonist series were investigated. This study showed that only small linear alkyl groups (methyl, propyl) are tolerated at the 2alpha-position of the piperidine ring of this series.