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1.
Mikrochim Acta ; 191(6): 297, 2024 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-38709347

RESUMO

A new detection platform based on a hydroxylated covalent organic framework (COF) integrated with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was constructed and used for detecting adrenergic receptor agonists (ARAs) residues in milk. The hydroxylated COF was prepared by polymerization of tris(4-aminophenyl)amine and 1,3,5-tris(4-formyl-3-hydroxyphenyl)benzene and applied to solid-phase extraction (SPE) of ARAs. This hydroxylated COF was featured with hierarchical flower-like morphology, easy preparation, and copious active adsorption sites. The adsorption model fittings and molecular simulation were applied to explore the potential adsorption mechanism. This detection platform was suitable for detecting four α2- and five ß2-ARAs residues in milk. The linear ranges of the ARAs were from 0.25 to 50 µg·kg-1; the intra-day and the inter-day repeatability were in the range 2.9-7.9% and 2.0-10.1%, respectively. This work demonstrates this hydroxylated COF has great potential as SPE cartridge packing, and provides a new way to determine ARAs residues in milk.


Assuntos
Leite , Extração em Fase Sólida , Espectrometria de Massas em Tandem , Extração em Fase Sólida/métodos , Leite/química , Animais , Espectrometria de Massas em Tandem/métodos , Hidroxilação , Estruturas Metalorgânicas/química , Adsorção , Agonistas Adrenérgicos/química , Agonistas Adrenérgicos/análise , Limite de Detecção , Bovinos
2.
Drug Dev Res ; 81(6): 716-727, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32359095

RESUMO

Ocular allergy is one of the most common disorders of the eye surface. The conventional eye drops lack of therapeutic efficacy due to low ocular bioavailability and decreased drug residence time on eye surface. Hence, the present research work aimed to formulate, optimize, and evaluate the in situ gel for ophthalmic drug delivery. The prepared in situ gel formulations were evaluated for clarity, pH, gelling capacity, viscosity, osmolality, in vitro release study, and kinetic evaluation. ex vivo corneal permeation/penetration study using goat and in vivo studies on rabbits were also performed. Fourier-transformed infrared spectroscopy was also applied to study possible interactions between drug and polymers. The formulations found to be stable, nonirritant, and showed sustained release of the drug for a period of up to 24 hr with no ocular damage. The developed in situ gels loaded with tetrahydrozoline are alternative and promising ocular candidates for the treatment of allergic conjunctivitis.


Assuntos
Agonistas Adrenérgicos/administração & dosagem , Conjuntivite Alérgica/tratamento farmacológico , Imidazóis/administração & dosagem , Descongestionantes Nasais/administração & dosagem , Agonistas Adrenérgicos/química , Animais , Córnea/efeitos dos fármacos , Córnea/metabolismo , Liberação Controlada de Fármacos , Géis , Imidazóis/química , Descongestionantes Nasais/química , Coelhos
3.
Int J Mol Sci ; 20(17)2019 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-31450631

RESUMO

Crosstalk between opioid and adrenergic receptors is well characterized and due to interactions between second messenger systems, formation of receptor heterodimers, and extracellular allosteric binding regions. Both classes of receptors bind both sets of ligands. We propose here that receptor crosstalk may be mirrored in ligand complementarity. We demonstrate that opioids bind to adrenergic compounds with micromolar affinities. Additionally, adrenergic compounds bind with micromolar affinities to extracellular loops of opioid receptors while opioids bind to extracellular loops of adrenergic receptors. Thus, each compound type can bind to the complementary receptor, enhancing the activity of the other compound type through an allosteric mechanism. Screening for ligand complementarity may permit the identification of other mutually-enhancing sets of compounds as well as the design of novel combination drugs or tethered compounds with improved duration and specificity of action.


Assuntos
Agonistas Adrenérgicos/química , Analgésicos Opioides/química , Desenvolvimento de Medicamentos , Receptores Adrenérgicos/química , Receptores Opioides/química , Agonistas Adrenérgicos/farmacologia , Analgésicos Opioides/farmacologia , Desenvolvimento de Medicamentos/métodos , Humanos , Cinética , Ligantes , Modelos Biológicos , Peptídeos/química , Peptídeos/metabolismo , Ligação Proteica , Receptores Opioides/agonistas , Relação Estrutura-Atividade
4.
J Nat Prod ; 81(4): 768-777, 2018 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-29517238

RESUMO

Isoquinoline alkaloids possess a wide range of structural features and pharmaceutical activities and are promising drug candidates. Ten water-soluble catecholic isoquinolines were isolated from the medicinal plant Portulaca oleracea, including three new (1-3) and seven known compounds (4-10), along with the known catecholamines 11 and 12 and four other known compounds (13-16). A method of polyamide column chromatography using EtOAc-MeOH as the mobile phase was developed for the isolation of catecholic isoquinolines. Alkaloids 1-12 exhibited anti-inflammatory activities (EC50 = 18.0-497.7 µM) through inhibition of NO production in lipopolysaccharide-induced murine macrophage RAW 264.7 cells. Among these compounds, 11, 2, 5, 4, and 8 were more potent than was the positive control, 3,4-dihydroxybenzohydroxamic acid (EC50 = 82.4 µM), with EC50 values of 18.0, 18.1, 35.4, 36.3, and 58.7 µM, respectively. Additionally, at 100 µM, compounds 1-12 showed different degrees of ß2-adrenergic receptor (ß2-AR) agonist activity in the CHO-K1/GA15 cell line which stably expressed ß2-AR as detected by a calcium assay. The EC50 values of 2 and 10 were 5.1 µM and 87.9 nM, respectively.


Assuntos
Agonistas Adrenérgicos/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/metabolismo , Anti-Inflamatórios/farmacologia , Isoquinolinas/farmacologia , Portulaca/química , Agonistas Adrenérgicos/química , Animais , Anti-Inflamatórios/química , Células CHO , Linhagem Celular , Cricetulus , Isoquinolinas/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Células RAW 264.7
5.
Int J Mol Sci ; 19(1)2018 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-29342106

RESUMO

Extensive evidence demonstrates functional interactions between the adrenergic and opioid systems in a diversity of tissues and organs. While some effects are due to receptor and second messenger cross-talk, recent research has revealed an extracellular, allosteric opioid binding site on adrenergic receptors that enhances adrenergic activity and its duration. The present research addresses whether opioid receptors may have an equivalent extracellular, allosteric adrenergic binding site that has similar enhancing effects on opioid binding. Comparison of adrenergic and opioid receptor sequences revealed that these receptors share very significant regions of similarity, particularly in some of the extracellular and transmembrane regions associated with adrenergic binding in the adrenergic receptors. Five of these shared regions from the mu opioid receptor (muOPR) were synthesized as peptides and tested for binding to adrenergic, opioid and control compounds using ultraviolet spectroscopy. Adrenergic compounds bound to several of these muOPR peptides with low micromolar affinity while acetylcholine, histamine and various adrenergic antagonists did not. Similar studies were then conducted with purified, intact muOPR with similar results. Combinations of epinephrine with methionine enkephalin or morphine increased the binding of both by about half a log unit. These results suggest that muOPR may be allosterically enhanced by adrenergic agonists.


Assuntos
Agonistas Adrenérgicos/metabolismo , Encefalina Metionina/metabolismo , Morfina/metabolismo , Domínios e Motivos de Interação entre Proteínas , Receptores Opioides mu/metabolismo , Acetilcolina/química , Acetilcolina/metabolismo , Agonistas Adrenérgicos/química , Sequência de Aminoácidos , Animais , Encefalina Metionina/química , Histamina/química , Histamina/metabolismo , Humanos , Metionina/química , Metionina/metabolismo , Camundongos , Morfina/química , Ligação Proteica , Receptores Adrenérgicos alfa 1/química , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Opioides mu/química , Espectrofotometria Ultravioleta
6.
Angew Chem Int Ed Engl ; 57(19): 5292-5295, 2018 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-29469969

RESUMO

The conformational complexity of transmembrane signaling of G-protein-coupled receptors (GPCRs) is a central hurdle for the design of screens for receptor agonists. In their basal states, GPCRs have lower affinities for agonists compared to their G-protein-bound active state conformations. Moreover, different agonists can stabilize distinct active receptor conformations and do not uniformly activate all cellular signaling pathways linked to a given receptor (agonist bias). Comparative fragment screens were performed on a ß2 -adrenoreceptor-nanobody fusion locked in its active-state conformation by a G-protein-mimicking nanobody, and the same receptor in its basal-state conformation. This simple biophysical assay allowed the identification and ranking of multiple novel agonists and permitted classification of the efficacy of each hit in agonist, antagonist, or inverse agonist categories, thereby opening doors to nanobody-enabled reverse pharmacology.


Assuntos
Agonistas Adrenérgicos/farmacologia , Antagonistas Adrenérgicos/farmacologia , Nanoestruturas/química , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Agonistas Adrenérgicos/química , Antagonistas Adrenérgicos/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Estrutura Molecular
7.
Luminescence ; 32(5): 706-712, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27900836

RESUMO

A new, simple, sensitive and rapid spectrofluorimetric method has been developed for determination of certain adrenergic agonists such as isoxsuprine hydrochloride, ritodrine hydrochloride and etilefrine hydrochloride in their pure forms and pharmaceutical dosage forms. The method depends on micellar enhancement of the native fluorescence of investigated drugs by using 2% w/v sodium dodecyl sulfate (SDS) as an anionic surfactant. The enhanced fluorescence intensity of investigated drugs was measured at 305 nm after excitation at 278 nm. The interaction of studied drugs with SDS was studied, and the enhanced fluorescence intensity was exploited to develop an assay method for the determination of investigated drugs. The relative fluorescence intensity-concentration plots were rectilinear over the range 0.15-3.00 µg ml-1 , with low quantification limits of 0.132, 0.123 and 0.118 µg mL-1 for isoxsuprine, ritodrine and etilefrine, respectively. The proposed method was successfully applied for determination of studied drugs in their pharmaceutical formulations. Moreover, the high sensitivity of the proposed method allows performing the content uniformity testing of the studied drugs in their tablets by using the official United States Pharmacopeia (USP) guidelines. Statistical comparisons of the results with those of the reported methods revealed excellent agreement and indicated no significant difference in accuracy and precision.


Assuntos
Agonistas Adrenérgicos/análise , Espectrometria de Fluorescência/métodos , Agonistas Adrenérgicos/química , Etilefrina/análise , Etilefrina/química , Concentração de Íons de Hidrogênio , Isoxsuprina/análise , Isoxsuprina/química , Reprodutibilidade dos Testes , Ritodrina/análise , Ritodrina/química , Sensibilidade e Especificidade , Dodecilsulfato de Sódio/química , Solventes/química , Tensoativos/química , Comprimidos/análise , Comprimidos/química , Temperatura , Fatores de Tempo
8.
J Org Chem ; 80(5): 2937-41, 2015 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-25689345

RESUMO

A novel methodology to produce highly enantioenriched N-(2-ethylamino)-ß-amino alcohols was developed. These compounds were obtained from O-(α-bromoacyl) cyanohydrins, which were synthesized by the minor enantiomer methodology employing a Lewis acid and a biocatalyst, followed by nucleophilic substitution with amines and reduction. The importance of the developed methodology was demonstrated by completing a highly enantioselective total synthesis of the ß3-adrenergic receptor agonist Solabegron.


Assuntos
Amino Álcoois/síntese química , Compostos de Anilina/síntese química , Benzoatos/síntese química , Compostos de Bifenilo/síntese química , Ácidos de Lewis/química , Nitrilas/química , Acilação , Agonistas Adrenérgicos/síntese química , Agonistas Adrenérgicos/química , Amino Álcoois/química , Compostos de Anilina/química , Benzoatos/química , Biocatálise , Compostos de Bifenilo/química , Estrutura Molecular , Estereoisomerismo
11.
J Biomol Struct Dyn ; 40(11): 5112-5127, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-33397209

RESUMO

Novel coronavirus (COVID-19) responsible for viral pneumonia which emerged in late 2019 has badly affected the world. No clinically proven drugs are available yet as the targeted therapeutic agents for the treatment of this disease. The viral main protease which helps in replication and transcription inside the host can be an effective drug target. In the present study, we aimed to discover the potential of ß-adrenoceptor agonists and adenosine deaminase inhibitors which are used in asthma and cancer/inflammatory disorders, respectively, as repurposing drugs against protease inhibitor by ligand-based and structure-based virtual screening using COVID-19 protease-N3 complex. The AARRR pharmacophore model was used to screen a set of 22,621 molecules to obtain hits, which were subjected to high-throughput virtual screening. Extra precision docking identified four top-scored molecules such as +/--fenoterol, FR236913 and FR230513 with lower binding energy from both categories. Docking identified three major hydrogen bonds with Gly143, Glu166 and Gln189 residues. 100 ns MD simulation was performed for four top-scored molecules to analyze the stability, molecular mechanism and energy requirements. MM/PBSA energy calculation suggested that van der Waals and electrostatic energy components are the main reasons for the stability of complexes. Water-mediated hydrogen bonds between protein-ligand and flexibility of the ligand are found to be responsible for providing extra stability to the complexes. The insights gained from this combinatorial approach can be used to design more potent and bio-available protease inhibitors against novel coronavirus.Communicated by Ramaswamy H. Sarma.


Assuntos
Inibidores de Adenosina Desaminase , Agonistas Adrenérgicos , Antivirais , Proteases 3C de Coronavírus , SARS-CoV-2 , Inibidores de Adenosina Desaminase/química , Inibidores de Adenosina Desaminase/farmacologia , Agonistas Adrenérgicos/química , Agonistas Adrenérgicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Reposicionamento de Medicamentos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Receptores Adrenérgicos , SARS-CoV-2/efeitos dos fármacos , Tratamento Farmacológico da COVID-19
12.
J Pharmacol Exp Ther ; 337(1): 256-66, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21233198

RESUMO

We define the pharmacological and pharmacokinetic profiles of a novel α(2C)-adrenoceptor agonist, compound A [N-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1,4-benzoxazin-6-yl]-N-ethyl-N'-methylurea]. This compound has high affinity (K(i)) for the human α(2C)-adrenoceptor (K(i) = 12 nM), and 190- to 260-fold selectivity over the α(2A)- and α(2B)-adrenoceptor subtypes. In cell-based functional assays, compound A produced good agonist (EC(50) = 166 nM) and efficacy (E(max) = 64%) responses at the α(2C)-adrenoceptor, much lower potency and efficacy at the α(2A)-adrenoceptor (EC(50) = 1525 nM; E(max) = 8%) and α(2B)-adrenoceptor (EC(50) = 5814 nM; E(max) = 21%) subtypes, and low or no affinity and functional activity at the α(1A)-, α(1B)-, and α(1D)-adrenoceptor subtypes. In the human saphenous vein postjunctional α(2C)-adrenoceptor bioassay, compound A functions as a potent agonist (pD(2) = 6.3). In a real-time contraction bioassay of pig nasal mucosa, compound A preferentially constricted the veins (EC(50) = 108 nM), and the magnitude of arteriolar contraction reached only 50% of the maximum venular responses. Compound A exhibited no effect on locomotor activity, sedation, and body temperature in mice (up to 100 mg/kg) and did not cause hypertension and mydriasis (30 mg/kg) in conscious rats. Compound A is orally bioavailable (24%) with good plasma exposure. This compound is a substrate for the efflux P-glycoprotein transporter, resulting in very low central nervous system (CNS) penetration. In summary, compound A is a highly selective, orally active, and non-CNS-penetrating α(2C)-adrenoceptor agonist with desirable in vitro and in vivo pharmacological properties suitable for the treatment of nasal congestion.


Assuntos
Agonistas Adrenérgicos/química , Agonistas Adrenérgicos/farmacologia , Compostos de Metilureia/química , Compostos de Metilureia/farmacologia , Morfolinas/química , Morfolinas/farmacologia , Atividade Motora/efeitos dos fármacos , Mucosa Nasal/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Veia Safena/efeitos dos fármacos , Agonistas Adrenérgicos/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Masculino , Compostos de Metilureia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Morfolinas/metabolismo , Atividade Motora/fisiologia , Mucosa Nasal/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/metabolismo , Veia Safena/metabolismo , Suínos
13.
Biomolecules ; 11(7)2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202543

RESUMO

Adrenergic receptors are G protein-coupled receptors for epinephrine and norepinephrine. They are targets of many drugs for various conditions, including treatment of hypertension, hypotension, and asthma. Adrenergic receptors are intensively studied in structural biology, displayed for binding poses of different types of ligands. Here, we summarized molecular mechanisms of ligand recognition and receptor activation exhibited by structure. We also reviewed recent advances in structure-based ligand discovery against adrenergic receptors.


Assuntos
Agonistas Adrenérgicos/química , Agonistas Adrenérgicos/metabolismo , Antagonistas Adrenérgicos/química , Antagonistas Adrenérgicos/metabolismo , Receptores Adrenérgicos/química , Receptores Adrenérgicos/metabolismo , Sequência de Aminoácidos , Animais , Cristalografia por Raios X/métodos , Epinefrina/química , Epinefrina/metabolismo , Humanos , Ligantes , Norepinefrina/química , Norepinefrina/metabolismo , Ligação Proteica/fisiologia , Conformação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Receptores Adrenérgicos/genética
14.
J Recept Signal Transduct Res ; 30(5): 304-12, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20836728

RESUMO

G protein-coupled receptors (GPCRs) initiate intracellular signaling pathways in response to physiologically and medically important extracellular ligands such as peptide and large glycoprotein hormones, neurotransmitters, sensory stimuli (odorant and taste molecules, light), calcium, l-amino acids, and are the target of many clinical drugs. The conversion of these extracellular stimuli into intracellular signals involves sequential and reversible reactions that initially take place at the plasma membrane. These reactions are mediated not only by dynamic interactions between ligands, receptors and heterotrimeric G proteins, but also by conformational changes associated with the activation/deactivation process of each protein. This review discusses the kinetic characteristics and rate-limiting reactions engaged in signal propagation that are involved in systems as diverse as neurotransmitter and hormonal signaling, and that have been recorded in live cells by Förster resonance energy transfer (FRET) approaches.


Assuntos
Membrana Celular/metabolismo , Receptores Acoplados a Proteínas G , Transdução de Sinais/fisiologia , Agonistas Adrenérgicos/química , Agonistas Adrenérgicos/metabolismo , Animais , Transferência Ressonante de Energia de Fluorescência , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo
15.
Planta Med ; 76(10): 981-6, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20217639

RESUMO

Synephrine and beta-phenethylamine, two naturally occurring compounds, are structurally related to ephedrine. In this study, the effects of synephrine and beta-phenethylamine on alpha-adrenergic receptor (alpha-AR) subtypes are investigated in human embryonic kidney (HEK293) or Chinese hamster ovary (CHO) cells, and compared to that of 1R,2S-norephedrine. The rank order of binding affinities was found to be the same for the subtypes tested (alpha(1A)-, alpha(2A)-, and alpha(2C)-AR) viz, 1R,2S-norephedrine > beta-phenethylamine > synephrine. Functional studies on the alpha(1A)-AR subtype showed that synephrine was a partial agonist giving a maximal response at 100 microM that was equal to 55.3 % of the L-phenylephrine maximum. In contrast, neither 1R,2S-norephedrine nor beta-phenethylamine exhibited agonist activity at the highest concentration tested (300 microM). beta-Phenethylamine was more potent as an antagonist than 1R,2S-norephedrine and synephrine on the alpha(1A)-AR subtype. Functional studies on the alpha(2A)- and alpha(2C)-AR subtypes indicated that synephrine and beta-phenethylamine did not act as agonists. Similar to 1R,2S-norephedrine, both of these analogs reversed the effect of medetomidine against forskolin-induced cAMP elevations at 300 microM, and the rank order of antagonist potency was: 1R,2S-norephedrine = beta-phenethylamine > synephrine; and beta-phenethylamine > 1R,2S-norephedrine > synephrine, respectively. These differences suggest that the presence of a 4-hydroxy group, as in synephrine, reduced the potency in these subtypes. In conclusion, at the alpha(1A)-AR, synephrine acted as a partial agonist, while beta-phenethylamine did not exhibit any direct agonist activity. Both, synephrine and beta-phenethylamine, may act as antagonists of pre-synaptic alpha(2A/2C)-ARs present in nerve terminals.


Assuntos
Agonistas Adrenérgicos/farmacologia , Antagonistas Adrenérgicos/farmacologia , Fenetilaminas/farmacologia , Extratos Vegetais/farmacologia , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Sinefrina/farmacologia , Agonistas Adrenérgicos/química , Antagonistas Adrenérgicos/química , Animais , Células CHO , Linhagem Celular , Colforsina/farmacologia , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Humanos , Medetomidina/farmacologia , Fenetilaminas/química , Fenilpropanolamina/farmacologia , Extratos Vegetais/química , Receptores Adrenérgicos alfa 1/química , Receptores Adrenérgicos alfa 2/química , Relação Estrutura-Atividade , Sinefrina/química
16.
Chem Pharm Bull (Tokyo) ; 58(4): 533-45, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20410638

RESUMO

In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential pharmacotherapies for the treatment of obesity and non-insulin dependent (type II) diabetes, we prepared a novel series of phenylethanolamine derivatives containing acetanilides and evaluated their biological activities at the human beta3-, beta2-, and beta1-ARs. Among these compounds, the 6-amino-2-pyridylacetanilide (36b), 2-amino-5-methylthiazol-4-ylacetanilide (36g), and 5-amino-1,2,4-thiadiazol-3-ylacetanilide (36h) derivatives showed potent agonistic activity at the beta3-AR with functional selectivity over the beta1- and beta2-ARs. In addition, these compounds exhibited significant hypoglycemic activity in a rodent diabetic model.


Assuntos
Agonistas Adrenérgicos/química , Agonistas Adrenérgicos/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 3 , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Fenetilaminas/química , Fenetilaminas/uso terapêutico , Agonistas Adrenérgicos/síntese química , Agonistas Adrenérgicos/farmacologia , Animais , Glicemia/efeitos dos fármacos , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Modelos Moleculares , Conformação Molecular , Fenetilaminas/síntese química , Fenetilaminas/farmacologia , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 3/metabolismo
17.
Biochem Pharmacol ; 171: 113731, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31783011

RESUMO

Stereoselectivity is well described for receptor binding and enzyme catalysis, but so far has only been scarcely investigated in carrier-mediated membrane transport. We thus studied transport kinetics of racemic (anti)adrenergic drugs by the organic cation transporters OCT1 (wild-type and allelic variants), OCT2, OCT3, MATE1, and MATE2-K with a focus on stereospecificity. OCT1 showed stereoselective uptake with up to 2-fold higher vmax over their corresponding counterpart enantiomers for (R,R)-fenoterol, (R,R)-formoterol, (S)-salbutamol, (S)-acebutolol, and (S)-atenolol. Orciprenaline and etilefrine were also transported stereoselectively. The Km was 2.1-fold and 1.5-fold lower for the (S,S)-enantiomers of fenoterol and formoterol, while no significant difference in Km was seen for the other aforementioned drugs. Common OCT1 variants showed similar enantiopreference to wild-type OCT1, with a few notable exceptions (e.g. a switch in enantiospecificity for fenoterol in OCT1*2 compared to the wild-type). Other cation transporters showed strong differences to OCT1 in stereoselectivity and transport activity: The closely related OCT2 displayed a 20-fold higher vmax for (S,S)-fenoterol compared to (R,R)-fenoterol and OCT2 and OCT3 showed 3.5-fold and 4.6-fold higher vmax for the pharmacologically active (R)-salbutamol over (S)-salbutamol. MATE1 and MATE2-K generally mediated transport with a higher capacity but lower affinity compared to OCT1, with moderate stereoselectivity. Our kinetic studies showed that significant stereoselectivity exists in solute carrier-mediated membrane transport of racemic beta-adrenergic drugs with surprising, and in some instances even opposing, preferences between closely related organic cation transporters. This may be relevant for drug therapy, given the strong involvement of these transporters in hepatic and renal drug elimination.


Assuntos
Agonistas Adrenérgicos/farmacologia , Antagonistas Adrenérgicos/farmacologia , Proteínas de Transporte de Cátions Orgânicos/agonistas , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Acebutolol/química , Acebutolol/metabolismo , Acebutolol/farmacologia , Agonistas Adrenérgicos/química , Agonistas Adrenérgicos/metabolismo , Antagonistas Adrenérgicos/química , Antagonistas Adrenérgicos/metabolismo , Atenolol/química , Atenolol/farmacologia , Transporte Biológico , Fenoterol/química , Fenoterol/metabolismo , Fenoterol/farmacologia , Fumarato de Formoterol/química , Fumarato de Formoterol/metabolismo , Fumarato de Formoterol/farmacologia , Células HEK293 , Humanos , Cinética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Transportador 1 de Cátions Orgânicos/agonistas , Transportador 1 de Cátions Orgânicos/antagonistas & inibidores , Transportador 1 de Cátions Orgânicos/metabolismo , Transportador 2 de Cátion Orgânico/agonistas , Transportador 2 de Cátion Orgânico/antagonistas & inibidores , Transportador 2 de Cátion Orgânico/metabolismo , Estereoisomerismo
18.
Bioorg Med Chem Lett ; 19(16): 4679-83, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19608416

RESUMO

As an extension of research, we have investigated modification of left-hand side (LHS) of biphenyl analogues containing an acylsulfonamide moiety in the development of potent and selective human beta(3)-adrenergic receptor (AR) agonists. Result of structure-activity relationships (SAR) and cassette-dosing evaluation in dogs showed that the hydroxynorephedrine analogue 16 had an excellent balance of in vitro and in vivo potency with pharmacokinetic profiles. In addition, to facilitate structure-based drug design (SBDD), we also have performed a docking study of biphenyl analogues based on the X-ray structure of the beta(2)-adrenergic receptor.


Assuntos
Agonistas Adrenérgicos/química , Agonistas de Receptores Adrenérgicos beta 3 , Receptores Adrenérgicos beta 2/química , Sulfonamidas/química , Agonistas Adrenérgicos/síntese química , Agonistas Adrenérgicos/farmacocinética , Animais , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Cães , Descoberta de Drogas , Humanos , Modelos Químicos , Receptores Adrenérgicos beta 3/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética
19.
Bioorg Med Chem ; 17(15): 5510-9, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19581100

RESUMO

In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, we prepared a novel series of phenoxypropanolamine derivatives containing the thiourea moiety and evaluated their biological activities at human beta3-, beta2-, and beta1-ARs. Among these compounds, 4-nitrophenylthiourea (18i) and 3-methoxyphenylthiourea (18k) derivatives were found to exhibit potent agonistic activity at the beta3-AR, with EC(50) values of 0.10 and 0.16 microM, respectively, and no agonistic activity for either the beta1- or beta2-AR. In addition, they showed significant hypoglycemic activity in a rodent diabetic model.


Assuntos
Agonistas Adrenérgicos/química , Agonistas Adrenérgicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Fenoxipropanolaminas/química , Fenoxipropanolaminas/uso terapêutico , Receptores Adrenérgicos beta/metabolismo , Agonistas Adrenérgicos/síntese química , Agonistas Adrenérgicos/farmacologia , Antagonistas de Receptores Adrenérgicos beta 3 , Animais , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Camundongos , Estrutura Molecular , Obesidade/tratamento farmacológico , Fenoxipropanolaminas/síntese química , Fenoxipropanolaminas/farmacologia , Receptores Adrenérgicos beta 3/metabolismo , Relação Estrutura-Atividade , Tioureia/síntese química , Tioureia/química , Tioureia/farmacologia , Tioureia/uso terapêutico
20.
Bioorg Med Chem Lett ; 18(18): 5037-40, 2008 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-18752946

RESUMO

Identification and SAR study of novel series of beta(3)-AR agonists with benzoic acid are described. Conversion of ether linkage position of phenoxybenzoic acid derivative 2b led to compound 7b with moderate beta(3)-AR activity. Further modification in right, center and left parts of compound 7b was investigated to improve the beta(3)-AR potency and selectivity. Compounds 7g and 7k, with the bulky aliphatic-substituted group at 2-position of benzoic acid moiety, were identified as potent and selective beta(3)-AR agonists. In addition, in vivo efficacy of compounds 7g and 7k was exhibited on dog OAB model.


Assuntos
Agonistas Adrenérgicos/síntese química , Agonistas Adrenérgicos/farmacologia , Agonistas de Receptores Adrenérgicos beta 3 , Benzoatos/síntese química , Benzoatos/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Agonistas Adrenérgicos/química , Animais , Benzoatos/química , Compostos de Bifenilo/química , Técnicas de Química Combinatória , Modelos Animais de Doenças , Cães , Humanos , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade
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