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1.
Bioorg Med Chem Lett ; 30(7): 126955, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32035698

RESUMO

This article describes the discovery of aryl hydroxy pyrimidinones and the medicinal chemistry efforts to optimize this chemotype for potent APJ agonism. APJ is a G-protein coupled receptor whose natural agonist peptide, apelin, displays hemodynamic improvement in the cardiac function of heart failure patients. A high throughput screen was undertaken to identify small molecule hits that could be optimized to mimic the apelin in vitro response. A potent and low molecular weight aryl hydroxy pyrimidinone analog 30 was identified through optimization of an HTS hit and medicinal chemistry efforts to improve its properties.

2.
Eur J Pharmacol ; 854: 1-8, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-30951717

RESUMO

Cannabinoid CB1 and CB2 receptors are activated by Δ9-tetrahydrocannabinol, a psychoactive component of marijuana. The cannabinoid CB1 receptor is primarily located in the brain and is responsible for the psychoactive side effects, whereas the cannabinoid CB2 receptor is located in immune cells and is an attractive target for immune-related maladies. We identify small molecules that selectively bind to the cannabinoid CB2 receptor and can be further developed into therapeutics. The affinity of three molecules, ABK5, ABK6, and ABK7, to the cannabinoid CB2 receptor was determined with radioligand competition binding. The potency of G-protein coupling was determined with GTPγS binding. The three compounds bound selectively to the cannabinoid CB2 receptor, and no binding to the cannabinoid CB1 receptor was detected up to 10 µM. Immunoblotting studies show that the amount of ERK1/2 and MEK phosphorylation increased in a Gi/o-dependent manner. Furthermore, an immune cell line (Jurkat cells) was treated with ABK5, and as a result, inhibited cell proliferation. These three compounds are novel cannabinoid CB2 receptor agonists and hold promise to be further developed to treat inflammation and the often-associated pain.


Assuntos
Receptor CB2 de Canabinoide/agonistas , Ligação Competitiva , Avaliação Pré-Clínica de Medicamentos , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Células HEK293 , Humanos , Células Jurkat , Ligantes , Receptor CB2 de Canabinoide/metabolismo
3.
Mol Pharmacol ; 93(2): 157-167, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29233847

RESUMO

Allosteric modulators of G protein-coupled receptors, including opioid receptors, have been proposed as possible therapeutic agents with enhanced selectivity. BMS-986122 is a positive allosteric modulator (PAM) of the µ-opioid receptor (µ-OR). BMS-986187 is a structurally distinct PAM for the δ-opioid receptor (δ-OR) that has been reported to exhibit 100-fold selectivity in promoting δ-OR over µ-OR agonism. We used ligand binding and second-messenger assays to show that BMS-986187 is an effective PAM at the µ-OR and at the κ-opioid receptor (κ-OR), but it is ineffective at the nociceptin receptor. The affinity of BMS-986187 for δ-ORs and κ-ORs is approximately 20- to 30-fold higher than for µ-ORs, determined using an allosteric ternary complex model. Moreover, we provide evidence, using a silent allosteric modulator as an allosteric antagonist, that BMS-986187 and BMS-986122 bind to a similar region on all three traditional opioid receptor types (µ-OR, δ-OR, and κ-OR). In contrast to the dogma surrounding allosteric modulators, the results indicate a possible conserved allosteric binding site across the opioid receptor family that can accommodate structurally diverse molecules. These findings have implications for the development of selective allosteric modulators.


Assuntos
Receptores Opioides delta/metabolismo , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Regulação Alostérica/efeitos dos fármacos , Sítio Alostérico , Animais , Células CHO , Linhagem Celular Tumoral , Cricetulus , Células HEK293 , Humanos , Antagonistas de Entorpecentes/farmacologia , Ensaio Radioligante , Ratos , Receptores Opioides delta/química , Receptores Opioides delta/efeitos dos fármacos , Receptores Opioides kappa/química , Receptores Opioides kappa/efeitos dos fármacos , Receptores Opioides mu/química , Receptores Opioides mu/efeitos dos fármacos , Sódio/metabolismo , Sulfonas/farmacologia , Xantonas/farmacologia
4.
SLAS Discov ; 23(4): 375-383, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29257918

RESUMO

The endocannabinoid system (ECS) plays a diverse role in human physiology ranging from the regulation of mood and appetite to immune modulation and the response to pain. Drug development that targets the cannabinoid receptors (CB1 and CB2) has been explored; however, success in the clinic has been limited by the psychoactive side effects associated with modulation of the neuronally expressed CB1 that are enriched in the CNS. CB2, however, are expressed in peripheral tissues, primarily in immune cells, and thus development of CB2-selective drugs holds the potential to modulate pain among other indications without eliciting anxiety and other undesirable side effects associated with CB1 activation. As part of a collaborative effort among industry and academic laboratories, we performed a high-throughput screen designed to discover selective agonists or positive allosteric modulators (PAMs) of CB2. Although no CB2 PAMs were identified, 167 CB2 agonists were discovered here, and further characterization of four select compounds revealed two with high selectivity for CB2 versus CB1. These results broaden drug discovery efforts aimed at the ECS and may lead to the development of novel therapies for immune modulation and pain management with improved side effect profiles.


Assuntos
Agonistas de Receptores de Canabinoides/farmacologia , Receptor CB2 de Canabinoide/agonistas , Animais , Células CHO , Cricetulus , Células HEK293 , Ensaios de Triagem em Larga Escala/métodos , Humanos , Dor/tratamento farmacológico , Dor/metabolismo , Receptor CB1 de Canabinoide/agonistas
5.
Assay Drug Dev Technol ; 15(7): 320-329, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29120673

RESUMO

Homogeneous functional assays that utilize competition binding technology are widely used for determining pharmacological properties such as intrinsic activity and potency. One example is time-resolved fluorescence resonance energy transfer (TR-FRET) 3',5'-cyclic adenosine monophosphate (cAMP) assays, where labeled cAMP (tracer) and a labeled anti-cAMP antibody bind together to produce a TR-FRET signal when the two constituents are proximal to each other. This signal is disrupted when unlabeled and cellularly generated cAMP competes with the tracer cAMP for binding to the labeled antibody. It is important that the resulting assay signal, usually expressed as a TR-FRET ratio, be transformed to cAMP concentration using a cAMP standard curve. However, examples are still generated in the literature wherein investigators have used the ratiometric signal (not transformed using a standard curve) to determine values for intrinsic activity and potency of ligands. Untransformed raw data often produce reasonable looking sigmoidal concentration response curves, perhaps tempting investigators to use the raw data instead of the transformed data for applying pharmacological models. In this article, we describe the correct procedure for determining the potency and intrinsic activity of ligands that result in changes in cAMP levels using a lysate dilution assay of GLP-1 (7-36)-mediated TR-FRET cAMP accumulation and simulated data. We also highlight how the inappropriate use of raw signal data can dramatically affect interpretation of intrinsic activity and potency of ligands, and how this can adversely affect drug discovery programs. These findings apply not only to cAMP functional assays but also to other functional cellular signaling assays that utilize competition binding technologies.


Assuntos
Ligação Competitiva/fisiologia , AMP Cíclico/metabolismo , Agonismo Parcial de Drogas , Transferência Ressonante de Energia de Fluorescência/métodos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Ligantes
6.
Nat Commun ; 8: 14611, 2017 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-28327612

RESUMO

Fear and emotional learning are modulated by endogenous opioids but the cellular basis for this is unknown. The intercalated cells (ITCs) gate amygdala output and thus regulate the fear response. Here we find endogenous opioids are released by synaptic stimulation to act via two distinct mechanisms within the main ITC cluster. Endogenously released opioids inhibit glutamate release through the δ-opioid receptor (DOR), an effect potentiated by a DOR-positive allosteric modulator. Postsynaptically, the opioids activate a potassium conductance through the µ-opioid receptor (MOR), suggesting for the first time that endogenously released opioids directly regulate neuronal excitability. Ultrastructural localization of endogenous ligands support these functional findings. This study demonstrates a new role for endogenously released opioids as neuromodulators engaged by synaptic activity to regulate moment-to-moment neuronal communication and excitability. These distinct actions through MOR and DOR may underlie the opposing effect of these receptor systems on anxiety and fear.


Assuntos
Tonsila do Cerebelo/metabolismo , Ansiedade/metabolismo , Medo/fisiologia , Interneurônios/metabolismo , Peptídeos Opioides/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Ácido Glutâmico/metabolismo , Técnicas In Vitro , Masculino , Técnicas de Patch-Clamp , Potássio/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Opioides/metabolismo , Sinapses/metabolismo
7.
J Pharmacol Exp Ther ; 356(2): 293-304, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26582730

RESUMO

The muscarinic acetylcholine receptor subtype 1 (M1) receptors play an important role in cognition and memory, and are considered to be attractive targets for the development of novel medications to treat cognitive impairments seen in schizophrenia and Alzheimer's disease. Indeed, the M1 agonist xanomeline has been shown to produce beneficial cognitive effects in both Alzheimer's disease and schizophrenia patients. Unfortunately, the therapeutic utility of xanomeline was limited by cholinergic side effects (sweating, salivation, gastrointestinal distress), which are believed to result from nonselective activation of other muscarinic receptor subtypes such as M2 and M3. Therefore, drug discovery efforts targeting the M1 receptor have focused on the discovery of compounds with improved selectivity profiles. Recently, allosteric M1 receptor ligands have been described, which exhibit excellent selectivity for M1 over other muscarinic receptor subtypes. In the current study, the following three compounds with mixed agonist/positive allosteric modulator activities that are highly functionally selective for the M1 receptor were tested in rats, dogs, and cynomologous monkeys: (3-((1S,2S)-2-hydrocyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)benzo[h]quinazolin-4(3H)-one; 1-((4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl)-4-oxo-4H-quinolizine-3-carboxylic acid; and (R)-ethyl 3-(2-methylbenzamido)-[1,4'-bipiperidine]-1'-carboxylate). Despite their selectivity for the M1 receptor, all three compounds elicited cholinergic side effects such as salivation, diarrhea, and emesis. These effects could not be explained by activity at other muscarinic receptor subtypes, or by activity at other receptors tested. Together, these results suggest that activation of M1 receptors alone is sufficient to produce unwanted cholinergic side effects such as those seen with xanomeline. This has important implications for the development of M1 receptor-targeted therapeutics since it suggests that dose-limiting cholinergic side effects still reside in M1 receptor selective activators.


Assuntos
Agonistas Muscarínicos/metabolismo , Agonistas Muscarínicos/farmacologia , Receptor Muscarínico M1/agonistas , Receptor Muscarínico M1/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Relação Dose-Resposta a Droga , Humanos , Macaca fascicularis , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley
8.
J Chem Inf Model ; 55(9): 1836-43, 2015 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-26347990

RESUMO

With the hope of discovering effective analgesics with fewer side effects, attention has recently shifted to allosteric modulators of the opioid receptors. In the past two years, the first chemotypes of positive or silent allosteric modulators (PAMs or SAMs, respectively) of µ- and δ-opioid receptor types have been reported in the literature. During a structure-guided lead optimization campaign with µ-PAMs BMS-986121 and BMS-986122 as starting compounds, we discovered a new chemotype that was confirmed to display µ-PAM or µ-SAM activity depending on the specific substitutions as assessed by endomorphin-1-stimulated ß-arrestin2 recruitment assays in Chinese Hamster Ovary (CHO)-µ PathHunter cells. The most active µ-PAM of this series was analyzed further in competition binding and G-protein activation assays to understand its effects on ligand binding and to investigate the nature of its probe dependence.


Assuntos
Descoberta de Drogas , Receptores Opioides mu/agonistas , Receptores Opioides mu/química , Regulação Alostérica , Animais , Células CHO , Cricetinae , Cricetulus , Sistemas de Liberação de Medicamentos , Ligantes , Modelos Biológicos , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologia , Tiazóis/química , Tiazóis/farmacologia
9.
Methods Mol Biol ; 1335: 223-40, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26260604

RESUMO

The continued evolution of our understanding of G protein-coupled receptor (GPCR) signaling has revealed new opportunities for drug discovery. Specifically, biased agonism at GPCRs and allosteric modulation of GPCRs both represent emerging areas of GPCR biology that hold promise for the development of novel GPCR-targeted therapeutics that may provide greater therapeutic efficacy and/or improved side-effect profiles. To obtain initial chemical leads, high-throughput screening (HTS) of a large compound library for the desired activity is often deployed during the early stages of a discovery program. The identification of allosteric modulators, in particular, poses significant challenges for HTS. We describe several HTS protocols designed for the identification of GPCR ligands, with a particular focus on the identification of allosteric modulators.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Receptores Acoplados a Proteínas-G/química , Receptores Acoplados a Proteínas-G/metabolismo , Regulação Alostérica/efeitos dos fármacos , Cálcio/metabolismo , Linhagem Celular , Receptores Acoplados a Proteínas-G/agonistas
10.
J Med Chem ; 58(10): 4220-9, 2015 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-25901762

RESUMO

Allosteric modulators of G protein-coupled receptors (GPCRs) have a number of potential advantages compared to agonists or antagonists that bind to the orthosteric site of the receptor. These include the potential for receptor selectivity, maintenance of the temporal and spatial fidelity of signaling in vivo, the ceiling effect of the allosteric cooperativity which may prevent overdose issues, and engendering bias by differentially modulating distinct signaling pathways. Here we describe the discovery, synthesis, and molecular pharmacology of δ-opioid receptor-selective positive allosteric modulators (δ PAMs). These δ PAMs increase the affinity and/or efficacy of the orthosteric agonists leu-enkephalin, SNC80 and TAN67, as measured by receptor binding, G protein activation, ß-arrestin recruitment, adenylyl cyclase inhibition, and extracellular signal-regulated kinases (ERK) activation. As such, these compounds are useful pharmacological tools to probe the molecular pharmacology of the δ receptor and to explore the therapeutic potential of δ PAMs in diseases such as chronic pain and depression.


Assuntos
Receptores Opioides delta/metabolismo , Relação Estrutura-Atividade , Animais , Arrestinas/metabolismo , Benzamidas/farmacologia , Ligação Competitiva , Células CHO , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Técnicas de Química Sintética , Cricetulus , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos/métodos , Encefalina Leucina/farmacologia , Ativação Enzimática/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Estrutura Molecular , Terapia de Alvo Molecular , Piperazinas/farmacologia , Ligação Proteica , Quinolinas/farmacologia , beta-Arrestinas
11.
J Biomol Screen ; 19(9): 1255-65, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25047277

RESUMO

Hetero-oligomeric complexes of G protein-coupled receptors (GPCRs) may represent novel therapeutic targets exhibiting different pharmacology and tissue- or cell-specific site of action compared with receptor monomers or homo-oligomers. An ideal tool for validating this concept pharmacologically would be a hetero-oligomer selective ligand. We set out to develop and execute a 1536-well high-throughput screen of over 1 million compounds to detect potential hetero-oligomer selective ligands using a ß-arrestin recruitment assay in U2OS cells coexpressing recombinant µ- and δ-opioid receptors. Hetero-oligomer selective ligands may bind to orthosteric or allosteric sites, and we might anticipate that the formation of hetero-oligomers may provide novel allosteric binding pockets for ligand binding. Therefore, our goal was to execute the screen in such a way as to identify positive allosteric modulators (PAMs) as well as agonists for µ, δ, and hetero-oligomeric receptors. While no hetero-oligomer selective ligands were identified (based on our selection criteria), this single screen did identify numerous µ- and δ-selective agonists and PAMs as well as nonselective agonists and PAMs. To our knowledge, these are the first µ- and δ-opioid receptor PAMs described in the literature.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Analgésicos Opioides/farmacologia , Ensaios de Triagem em Larga Escala , Receptores Opioides delta/agonistas , Receptores Opioides delta/química , Receptores Opioides mu/agonistas , Receptores Opioides mu/química , Animais , Arrestinas/metabolismo , Células CHO , Colforsina/farmacologia , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Antagonistas de Entorpecentes/farmacologia , Multimerização Proteica , beta-Arrestinas
12.
Proc Natl Acad Sci U S A ; 110(26): 10830-5, 2013 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-23754417

RESUMO

µ-Opioid receptors are among the most studied G protein-coupled receptors because of the therapeutic value of agonists, such as morphine, that are used to treat chronic pain. However, these drugs have significant side effects, such as respiratory suppression, constipation, allodynia, tolerance, and dependence, as well as abuse potential. Efforts to fine tune pain control while alleviating the side effects of drugs, both physiological and psychological, have led to the development of a wide variety of structurally diverse agonist ligands for the µ-opioid receptor, as well as compounds that target κ- and δ-opioid receptors. In recent years, the identification of allosteric ligands for some G protein-coupled receptors has provided breakthroughs in obtaining receptor subtype-selectivity that can reduce the overall side effect profiles of a potential drug. However, positive allosteric modulators (PAMs) can also have the specific advantage of only modulating the activity of the receptor when the orthosteric agonist occupies the receptor, thus maintaining spatial and temporal control of receptor signaling in vivo. This second advantage of allosteric modulators may yield breakthroughs in opioid receptor research and could lead to drugs with improved side-effect profiles or fewer tolerance and dependence issues compared with orthosteric opioid receptor agonists. Here, we describe the discovery and characterization of µ-opioid receptor PAMs and silent allosteric modulators, identified from high-throughput screening using a ß-arrestin-recruitment assay.


Assuntos
Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismo , Sulfonas/farmacologia , Tiazóis/farmacologia , Regulação Alostérica , Sítio Alostérico , Animais , Arrestinas/metabolismo , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , Descoberta de Drogas , Ensaios de Triagem em Larga Escala , Humanos , Ligantes , Ratos , Sulfonas/química , Tiazóis/química , beta-Arrestinas
13.
Assay Drug Dev Technol ; 10(5): 457-67, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22746835

RESUMO

In recent years, the increased use of cell-based functional assays for G protein-coupled receptors in high-throughput screening has enabled the design of robust assays to identify allosteric modulators (AMs) in addition to the more traditional orthosteric agonists and antagonists. In this article, the authors describe a screening format able to identify all ligand types using a triple-add assay that measures changes in cytosolic calcium concentration with three separate additions and reads in the same assay plate. This triple-add assay captures more small molecule ligand types than previously described assay formats without a significant increase in screening cost. Finally, the customizability of the triple-add assay to suit the needs of various AM screening programs is demonstrated.


Assuntos
Sinalização do Cálcio/fisiologia , Ensaios de Triagem em Larga Escala/métodos , Receptores Acoplados a Proteínas-G/fisiologia , Regulação Alostérica/fisiologia , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Ligantes , Ligação Proteica/fisiologia
14.
ACS Comb Sci ; 14(3): 197-204, 2012 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-22340081

RESUMO

We have developed a solid phase synthesis route to 1,5-substituted pyrazole-4-carboxamides with three diversity points aimed at the discovery of new compounds as potential G-Protein coupled receptor (GPCR) ligands. The new chemistry involves acylation of a resin bound secondary amine with a ß-ketoester via transamidation, conversion of the resulting ß-ketoamide to the corresponding vinylogous amide, pyrazole formation upon reaction with a aryl hydrzine, and cleavage of the product from the resin. Using the reported methodology, we describe the syntheses of multiple arrays of pyrazoles that were used collectively to construct a library of more than 1000 analogues. Several members of this library displayed submicromolar antagonist activities at the cannabinoid subtype 1 (CB-1) receptor.


Assuntos
Amidas/química , Descoberta de Drogas , Pirazóis/química , Receptor CB1 de Canabinoide/antagonistas & inibidores , Amidas/farmacologia , Concentração Inibidora 50 , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/química , Técnicas de Síntese em Fase Sólida
16.
Biochem Pharmacol ; 81(6): 691-702, 2011 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-21184747

RESUMO

Once considered a pharmacological curiosity, allosteric modulation of seven transmembrane domain G-protein-coupled receptors (GPCRs) has emerged as a potentially powerful means to affect receptor function for therapeutic purposes. Allosteric modulators, which interact with binding sites topologically distinct from the orthosteric ligand binding sites, can potentially provide improved selectivity and safety, along with maintenance of spatial and temporal aspects of GPCR signaling. Accordingly, drug discovery efforts for GPCRs have increasingly focused on the identification of allosteric modulators. This review is devoted to an examination of the strategies, challenges, and opportunities for high-throughput screening for allosteric modulators of GPCRs, with particular focus on the identification of positive allosteric modulators.


Assuntos
Regulação Alostérica/fisiologia , Descoberta de Drogas/métodos , Receptores Acoplados a Proteínas-G/química , Receptores Acoplados a Proteínas-G/metabolismo , Regulação Alostérica/efeitos dos fármacos , Sítio Alostérico/efeitos dos fármacos , Sítio Alostérico/fisiologia , Animais , Descoberta de Drogas/tendências , Humanos , Ligantes
17.
Bioorg Med Chem Lett ; 17(14): 3978-82, 2007 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-17513109

RESUMO

Structure-activity relationships for a series of pyrazine carboxamide CB1 antagonists are reported. Pharmaceutical properties of the series are improved via inclusion of hydroxyl-containing sidechains. This structural modification sufficiently improved ADME properties of an orally inactive series such that food intake reduction was achieved in rat feeding models. Compound 35 elicits a 46% reduction in food intake in ad libidum fed rats 4-h post-dose.


Assuntos
Amidas/farmacologia , Pirazinamida/análogos & derivados , Receptor CB1 de Canabinoide/antagonistas & inibidores , Amidas/química , Animais , Pirazinamida/química , Pirazinamida/farmacologia , Ratos , Relação Estrutura-Atividade
18.
J Med Chem ; 47(7): 1704-8, 2004 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-15027861

RESUMO

A novel series of dihydro- and tetrahydrotriazolopyridazine-1,3-dione-based amino acid derivatives were identified as very potent motilin receptor agonists. Incorporating one additional phenylethyl glycinamide subunit to 1 (EC(50) = 660 nM) was found to improve in vitro potency approximately 3000-fold, resulting in compound 10 (EC(50) = 0.22 nM). The more potent enantiomer 11A has an EC(50) of 0.047 nM in the motilin receptor functional assay and a K(i) of 0.7 nM in the binding assay. In addition, compound 11A was shown to have a significantly reduced tendency to cause receptor desensitization as compared with the motilin receptor agonist ABT-229.


Assuntos
Motilina/agonistas , Piridazinas/síntese química , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores de Neuropeptídeos/agonistas , Triazóis/síntese química , Sinalização do Cálcio/efeitos dos fármacos , Células HeLa , Humanos , Piridazinas/química , Piridazinas/farmacologia , Receptores dos Hormônios Gastrointestinais/metabolismo , Receptores de Neuropeptídeos/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologia
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