RESUMO
A new series of potent fused thiazole mGlu5 receptor positive allosteric modulators (PAMs) (10, 11 and 27-31) are disclosed and details of the SAR and optimization are described. Optimization of alkynyl thiazole 9 (Lu AF11205) led to the identification of potent fused thiazole analogs 10b, 27a, 28j and 31d. In general, substituted cycloalkyl, aryl and heteroaryl carboxamides, and carbamate analogs are mGlu5PAMs, whereas smaller alkyl carboxamide, sulfonamide and sulfamide analogs tend to be mGlu5 negative allosteric modulators (NAMs).
Assuntos
Alcinos/química , Receptor de Glutamato Metabotrópico 5/química , Tiazóis/química , Regulação Alostérica , Amidas/síntese química , Amidas/química , Amidas/metabolismo , Carbamatos/síntese química , Carbamatos/química , Carbamatos/metabolismo , Humanos , Ligação Proteica , Receptor de Glutamato Metabotrópico 5/metabolismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/metabolismoRESUMO
A novel series of trans-1,3-cyclohexyl diamides was discovered and characterized as mGluR5 negative allosteric modulators (NAMs) lacking an alkyne moiety. Conformational constraint of one of the amide bonds in the diamide template led to a spirooxazoline template. A representative compound (24d) showed good in vitro potency, high CNS penetration and, upon subcutaneous dosing, demonstrated efficacy in the mouse marble burying test, generally used as indicative of potential anxiolytic activity.
Assuntos
Amidas/química , Amidas/farmacologia , Cicloexanos/química , Cicloexanos/farmacologia , Receptor de Glutamato Metabotrópico 5/química , Regulação Alostérica , Amidas/síntese química , Amidas/farmacocinética , Animais , Cicloexanos/síntese química , Cicloexanos/farmacocinética , Células HEK293 , Humanos , Camundongos , Modelos Moleculares , Conformação Molecular , Receptor de Glutamato Metabotrópico 5/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel series of aryl azetidinyl oxadiazoles are identified as mGluR5 positive allosteric modulators (PAMs) with improved physico-chemical properties. N-substituted cyclohexyl and exo-norbornyl carboxamides, and carbamate analogs of azetidines are moderate to potent mGluR5 PAMs. The aryl, lower alkyl carboxamides analogs and sulfonamide analogs of azetidines are moderate mGluR5 negative allosteric modulators (NAMs). In the aryl oxadiazole moiety, substituents such as fluoro, chloro and methyl are well tolerated at the meta position while para substituents led to either inactive compounds or NAMs. A tight pharmacophore and subtle 'PAM to NAM switching' with close analogs makes the optimization of the series extremely challenging.
Assuntos
Regulação Alostérica/efeitos dos fármacos , Azetidinas/química , Azetidinas/farmacologia , Oxidiazóis/química , Oxidiazóis/farmacologia , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Azetidinas/metabolismo , Azetidinas/farmacocinética , Humanos , Oxidiazóis/metabolismo , Oxidiazóis/farmacocinética , Ratos , Receptor de Glutamato Metabotrópico 5 , Relação Estrutura-AtividadeRESUMO
A novel series of N-aryl pyrrolidinonyl oxadiazoles were identified as mGluR5 positive allosteric modulators (PAMs). Optimization of the initial lead compound 6a led to the identification of the 12c (-) enantiomer as a potent compound with acceptable in vitro clearance, CYP, hERG and PK properties. Para substituted N-aryl pyrrolidinonyl oxadiazoles are mGluR5 PAMs while the meta and ortho substituted N-aryl pyrrolidinonyl oxadiazoles are negative allosteric modulators (NAMs). Para fluoro substitution on the N-aryl group and meta chloro or methyl substituents on the aryl oxadiazole moiety are optimal for mGluR5 PAM efficacy. The existence of an exquisitely sensitive 'PAM to NAM switch' within this chemotype making it challenging for simultaneous optimization of potency and drug-like properties.
Assuntos
Oxidiazóis/química , Oxidiazóis/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/metabolismo , Regulação Alostérica , Animais , Linhagem Celular , Humanos , Oxidiazóis/farmacocinética , Pirrolidinas/farmacocinética , Ratos , Receptor de Glutamato Metabotrópico 5 , Relação Estrutura-AtividadeRESUMO
BACKGROUND: P2X7 receptor antagonists have potential for treating various central nervous system (CNS) diseases, including neuropathic pain, although none have been approved for clinical use. Reasons may include insufficient understanding of P2X7 receptor signalling in pain, and the lack of a corresponding preclinical mechanistic biomarker. METHODS: Lu AF27139 is a highly selective and potent small molecule antagonist at rat, mouse and human forms of the P2X7 receptor, with excellent pharmacokinetic and CNS permeability properties. In the current experiments, we probed the utility of previously characterized and novel signalling cascades exposed to Lu AF27139 using cultured microglia combined with release assays. Subsequently, we assessed the biomarker potential of identified candidate molecules in the rat chronic constriction injury (CCI) model of neuropathic pain; study design limitations precluded their assessment in spared nerve injury (SNI) rats. RESULTS: Lu AF27139 blocked several pain-relevant pathways downstream of P2X7 receptors in vitro. At brain and spinal cord receptor occupancy levels capable of functionally blocking P2X7 receptors, it diminished neuropathic hypersensitivity in SNI rats, and less potently in CCI rats. Although tissue levels of numerous molecules previously linked to neuropathic pain and P2X7 receptor function (e.g. IL-6, IL-1ß, cathepsin-S, 2-AG) were unaffected by CCI, Lu AF27139-mediated regulation of spinal PGE2 and miRNA (e.g. rno-miR-93-5p) levels increased by CCI aligned with its ability to diminish neuropathic hypersensitivity. CONCLUSIONS: We have identified a pain-relevant P2X7 receptor-regulated mechanism in neuropathic rats, which could hold promise as a translatable biomarker and by association enhance the clinical progression of P2X7 receptor antagonists in neuropathic pain. SIGNIFICANCE: Sub-optimal translation of preclinical molecules has hindered the clinical development of novel mechanism of action analgesics. We have undertaken a comprehensive in vitro analysis of migroglial signalling mechanisms recruited upon P2X7 receptor activation, a number of which were shown to be modulated by a selective P2X7 receptor antagonist in a well characterized animal model of neuropathic pain. Subject to further confirmation in other neuropathic models, this opens up the possibility to investigate their clinical utility as potential pain biomarkers in patients.
Assuntos
Hipersensibilidade , MicroRNAs , Neuralgia , Antagonistas do Receptor Purinérgico P2X , Receptores Purinérgicos P2X7 , Animais , Hipersensibilidade/metabolismo , MicroRNAs/metabolismo , Microglia/metabolismo , Neuralgia/metabolismo , Prostaglandinas/metabolismo , Antagonistas do Receptor Purinérgico P2X/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2X7/metabolismo , Medula Espinal/metabolismoRESUMO
A series of metabotropic glutamate 5 receptor (mGluR5) allosteric ligands with positive, negative or no modulatory efficacy is described. The ability of this series to yield both mGluR5 PAMs and NAMs with single-digit nanomolar potency is unusual, and the underlying SAR is detailed.
Assuntos
Desenho de Fármacos , Receptores de Glutamato Metabotrópico/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Regulação Alostérica , Concentração Inibidora 50 , Ligantes , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Receptor de Glutamato Metabotrópico 5 , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-AtividadeRESUMO
This Letter describes the discovery of a novel series of mGluR5 positive allosteric modulators (PAMs). The lead compound, 11c, exhibits excellent potency (EC(50)=30 nM) in vitro, and reaches high brain levels in both rats and mice after oral administration.
Assuntos
Alcinos/química , Encéfalo/metabolismo , Compostos Heterocíclicos/química , Receptores de Glutamato Metabotrópico/agonistas , Administração Oral , Alcinos/farmacologia , Regulação Alostérica , Animais , Descoberta de Drogas , Compostos Heterocíclicos/farmacologia , Camundongos , Ratos , Receptor de Glutamato Metabotrópico 5 , Relação Estrutura-AtividadeRESUMO
The complement system represents an innate immune mechanism of host defense that has three effector arms, the C3a receptor, the C5a receptor (C5aR), and the membrane attack complex. Because of its inflammatory and immune-enhancing properties, the biological activity of C5a and its classical receptor have been widely studied. Because specific antagonism of the C5aR could have therapeutic benefit without affecting the protective immune response, the C5aR continues to be a promising target for pharmaceutical research. The lack of specific, potent and orally bioavailable small-molecule antagonists has limited the clinical investigation of the C5aR. We report the discovery of NDT 9513727 [N,N-bis(1,3-benzodioxol-5-ylmethyl)-1-butyl-2,4-diphenyl-1H-imidazole-5-methanamine], a small-molecule, orally bioavailable, selective, and potent inverse agonist of the human C5aR. NDT 9513727 was discovered based on the integrated use of in vitro affinity and functional assays in conjunction with medicinal chemistry. NDT 9513727 inhibited C5a-stimulated responses, including guanosine 5'-3-O-(thio)triphosphate binding, Ca(2+) mobilization, oxidative burst, degranulation, cell surface CD11b expression and chemotaxis in various cell types with IC(50)s from 1.1 to 9.2 nM, respectively. In C5a competition radioligand binding experiments, NDT 9513727 exhibited an IC(50) of 11.6 nM. NDT 9513727 effectively inhibited C5a-induced neutropenia in gerbil and cynomolgus macaque in vivo. The findings suggest that NDT 9513727 may be a promising new entity for the treatment of human inflammatory diseases.
Assuntos
Benzodioxóis/farmacologia , Imidazóis/farmacologia , Receptor da Anafilatoxina C5a/agonistas , Animais , Antígeno CD11b/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Degranulação Celular/efeitos dos fármacos , Linhagem Celular , Quimiotaxia/efeitos dos fármacos , Gerbillinae , Humanos , Macaca , Neutropenia/induzido quimicamente , Ligação Proteica , Explosão Respiratória/efeitos dos fármacosRESUMO
The design, synthesis and structure-activity relationship studies of a novel series of CRF-1 receptor antagonists, the 2-arylpyrimidines, are described. The effects of substitution on the aromatic ring and the pyrimidine core on CRF-1 receptor binding were investigated. A number of compounds with K(i) values below 10 nM and lipophilicity in a minimally acceptable range for a CNS drug (cLogP<5) were discovered.
Assuntos
Química Farmacêutica/métodos , Pirimidinas/química , Pirimidinas/síntese química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Sítios de Ligação , Química Farmacêutica/instrumentação , Desenho de Fármacos , Humanos , Cinética , Modelos Químicos , Conformação Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Solubilidade , Relação Estrutura-AtividadeRESUMO
A series of 5,6-diaryl-2-amino-pyrazines were prepared and found to have antagonist-like properties at the CB1 receptor. Subsequent SAR studies optimized both receptor potency and drug-like properties including solubility and Cytochrome-P450 inhibition potential. Optimized compounds were demonstrated to be inverse agonists and compared in vivo with rimonabant for their ability to inhibit food intake, to occupy central CB1 receptors and to influence hormonal markers associated with obesity.
Assuntos
Pirazinas/síntese química , Pirazinas/farmacologia , Receptor CB1 de Canabinoide/agonistas , Animais , Glicemia/análise , Técnicas de Química Combinatória , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Modelos Animais de Doenças , Comportamento Alimentar/efeitos dos fármacos , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Obesidade/metabolismo , Piperidinas/farmacologia , Pirazinas/sangue , Pirazóis/farmacologia , Ratos , Receptor CB1 de Canabinoide/sangue , Rimonabanto , Relação Estrutura-AtividadeRESUMO
The design, synthesis and structure-activity relationships of a novel series of CRF-1 receptor antagonist, the 1-aryl-4-alkylaminoisoquinolines, is described. The effects of substitution on the aromatic ring, the amino group and the isoquinoline core on CRF-1 receptor binding were investigated.
Assuntos
Desenho de Fármacos , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Ansiedade/tratamento farmacológico , Sítios de Ligação , Técnicas de Química Combinatória , Depressão/tratamento farmacológico , Humanos , Isoquinolinas/química , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Drug design necessitates a clear understanding of the phenotypic response to be elicited by a given ligandtarget interaction. This relationship is relatively well understood for classical biological targets of drug action, but for some novel targets, notably those amenable to allosteric modulation, developing such understanding may represent a more challenging task. In order to gain knowledge on the nature of the functional response derived from mGlu4 receptor activation, its molecular and cell biology are reviewed, including signalling pathways involved, receptor localization in central nervous system and beyond, and potential genetic links to disease. Broadly held views for both, orthosteric agonists as well as allosteric modulators, are compared with specific observations for the case of mGlu4 receptor activation via orthosteric and allosteric mechanisms. First, sub-type selectivity and brain penetration of amino acid mGlu4 receptor agonists are discussed, followed by the quantification of functional allosteric effects, the potential role of heterodimers in the functional response, and the observation of supra-physiological efficacy of mGlu4 receptor PAMs. We show that, in our analysis, these attributes differ from those that may be expected by extrapolating from broad knowledge. In addition, recent progress with mGlu4 receptor radioligands and PET ligands is summarized.
Assuntos
Sistema Nervoso Central/metabolismo , Doenças Neurodegenerativas/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Bibliotecas de Moléculas Pequenas/química , Regulação Alostérica , Sítio Alostérico , Transporte Biológico , Sistema Nervoso Central/patologia , Desenho de Fármacos , Regulação da Expressão Gênica , Humanos , Canais Iônicos/genética , Canais Iônicos/metabolismo , Ligantes , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Multimerização Proteica , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/química , Receptores de Glutamato Metabotrópico/genética , Transdução de Sinais , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-AtividadeRESUMO
The design, synthesis, and structure-activity relationships of a novel series of pyrazines, acting as corticotropin releasing factor-1 (CRF-1) receptor antagonists, are described. Synthetic methodologies were developed to prepare a number of substituted pyrazine cores utilizing regioselective halogenation and chemoselective derivatization. Noteworthy, an efficient 5-step synthesis was developed for the lead compound 59 (NGD 98-2), which required no chromatography. Compound 59 was characterized as an orally bioavailable, brain penetrant, and highly selective CRF-1 receptor antagonist. Occupancy of rat brain CRF-1 receptors was quantified using ex vivo receptor occupancy assays, using both brain tissue homogenates as well as brain slices receptor autoradiography. Behaviorally, oral administration of 59 significantly antagonized CRF-induced locomotor activity at doses as low as 10 mg/kg and dose-dependently reduced the restraint stress-induced ACTH increases.
Assuntos
Pirazinas/síntese química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Tecido Adiposo/metabolismo , Administração Oral , Hormônio Adrenocorticotrópico/sangue , Animais , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Córtex Cerebral/metabolismo , Humanos , Técnicas In Vitro , Injeções Intraventriculares , Masculino , Microssomos Hepáticos/metabolismo , Atividade Motora/efeitos dos fármacos , Pirazinas/química , Pirazinas/farmacologia , Ensaio Radioligante , Ratos , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Restrição Física , Relação Estrutura-AtividadeRESUMO
Metabotropic glutamate receptor 5 (mGlu5) negative allosteric modulators (NAMs) have previously been implicated in a number of pathophysiological conditions, based on preclinical, and to some extent clinical, proof of concept for migraine, gastroesophageal reflux disease, Parkinson's disease and anxiety. In the past, the potential use of known mGlu5 antagonists for the treatment of lower urinary tract disorders was disclosed. In the patent evaluated herein, novel derivatives of 4-(prop-2-ynylidene)piperidine are described and claimed by Recordati Ireland Ltd, Ireland, as NAMs at mGlu5 for the treatment of lower urinary tract disorders. Selected compounds reported in this application were efficacious in the cystometry model of bladder dysfunction in conscious rats, and mGlu5 NAMs are, therefore, suggested to have potential for the treatment of lower urinary tract disorders.
Assuntos
Piperidinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Doenças Urológicas/tratamento farmacológico , Regulação Alostérica , Animais , Modelos Animais de Doenças , Desenho de Fármacos , Humanos , Patentes como Assunto , Piperidinas/química , Ratos , Receptor de Glutamato Metabotrópico 5 , Doenças Urológicas/fisiopatologiaRESUMO
BACKGROUND: Distinct pathways of leukocyte activation during simulated cardiopulmonary bypass are mediated by the complement C5a anaphylatoxin. We hypothesized that a human C5a receptor antagonist would specifically inhibit the inflammatory response of neutrophils to simulated extracorporeal circulation, while preserving the C5b-9 pathway for innate immunity. METHODS: An in vitro extracorporeal circuit recirculated fresh heparinized whole blood through a membrane oxygenator with and without addition of a small molecule human C5a receptor antagonist. Samples were periodically drawn over 90 minutes for complement and leukocyte activation studies. RESULTS: Addition of the C5a receptor antagonist to simulated extracorporeal circulation abrogated both neutrophil CD11b upregulation and interleukin 8 release (p < 0.01 for both), despite full generation of C3a and C5b-9; however, elastase release from neutrophils was unaffected. Although C5a receptor blockade only trended toward inhibiting monocyte CD11b upregulation (p = 0.09), circuit clearance of both monocytes (p = 0.04) and neutrophils (p = 0.01) was significantly decreased. In addition, the C5a receptor antagonist completely blocked both neutrophil-platelet and monocyte-platelet conjugate formation (p < 0.001 for both), without affecting platelet P-selectin expression. CONCLUSIONS: C5a receptor blockade during simulated extracorporeal circulation completely blocked neutrophil beta2 integrin upregulation and induction of plasma interleukin 8, suggesting an acute downregulatory effect on neutrophil chemotaxis-related pathways, while preserving terminal complement generation and neutrophil elastase release. Inhibition of leukocyte-platelet conjugate formation suggests a novel function for leukocyte adhesive receptors, possibly related to preservation of elastase generation.
Assuntos
Ponte Cardiopulmonar , Leucócitos/efeitos dos fármacos , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Plaquetas/efeitos dos fármacos , Antígeno CD11b/análise , Ativação do Complemento/efeitos dos fármacos , Humanos , Interleucina-8/análise , Elastase de Leucócito/fisiologia , Neutrófilos/efeitos dos fármacosRESUMO
Anaphylatoxin C5a is a potent inflammatory mediator associated with pathogenesis and progression of several inflammation-associated disorders. Small molecule C5a receptor (C5aR) antagonist development is hampered by species-specific receptor biology and the associated inability to use standard rat and mouse in vivo models. Gerbil is one rodent species reportedly responsive to small molecule C5aR antagonists with human C5aR affinity. We report the identification of the gerbil C5aR cDNA using a degenerate primer PCR cloning strategy. The nucleotide sequence revealed an open reading frame encoding a 347-amino acid protein. The cloned receptor (expressed in Sf9 cells) bound recombinant human C5a with nanomolar affinity. Alignment of the gerbil C5aR sequence with those from other species showed that a Trp residue in transmembrane domain V is the only transmembrane domain amino acid unique to small molecule C5aR antagonist-responsive species (i.e. gerbil, human, and non-human primate). Site-directed mutagenesis was used to generate human and mouse C5aRs with a residue exchange of this Trp residue. Mutation of Trp to Leu in human C5aR completely eliminated small molecule antagonist-receptor interaction. In contrast, mutation of Leu to Trp in mouse C5aR enabled small molecule antagonist-receptor interaction. This crucial Trp residue is located deeper within transmembrane domain V than residues reportedly involved in C5a- and cyclic peptide C5a antagonist-receptor interaction, suggesting a novel interaction site(s) for small molecule antagonists. These data provide insight into the basis for small molecule antagonist species selectivity and further define sites critical for C5aR activation and function.
Assuntos
Membrana Celular/química , Gerbillinae , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Receptor da Anafilatoxina C5a/química , Triptofano , Sequência de Aminoácidos , Animais , Sequência de Bases , Sítios de Ligação , Clonagem Molecular , Expressão Gênica , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Camundongos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Ratos , Receptor da Anafilatoxina C5a/genética , Alinhamento de Sequência , Especificidade da Espécie , Relação Estrutura-AtividadeRESUMO
The synthesis of a series of 3-aryl pyrazolo[4,3-d]pyrimidines as potential corticotropin-releasing factor (CRF-1) antagonists is described. The effects of substitution on the aromatic ring, the amino group and the pyrazolo ring on CRF-1 receptor binding were investigated.
Assuntos
Desenho de Fármacos , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Sítios de Ligação , Estrutura Molecular , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
A series of chiral benzylpiperazinyl-1-(2,3-dihydro-indol-1-yl)ethanone derivatives were prepared and examined for their affinity at dopamine D(2) and D(4) receptors. Three compounds having D(2)/D(4) affinity ratios approximating that found for the atypical neuroleptic clozapine were further evaluated in behavioral tests of antipsychotic efficacy and motor side effects.
Assuntos
Antagonistas de Dopamina/síntese química , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Indóis/síntese química , Indóis/farmacologia , Piperazinas/síntese química , Piperazinas/farmacologia , Anfetamina/antagonistas & inibidores , Anfetamina/farmacologia , Animais , Antipsicóticos/metabolismo , Antipsicóticos/farmacologia , Ligação Competitiva/efeitos dos fármacos , Catalepsia/induzido quimicamente , Estimulantes do Sistema Nervoso Central/antagonistas & inibidores , Estimulantes do Sistema Nervoso Central/farmacologia , Clozapina/metabolismo , Clozapina/farmacologia , Antagonistas de Dopamina/toxicidade , Avaliação Pré-Clínica de Medicamentos , Discinesia Induzida por Medicamentos/psicologia , Meia-Vida , Haloperidol/farmacologia , Humanos , Técnicas In Vitro , Indicadores e Reagentes , Indóis/toxicidade , Atividade Motora/efeitos dos fármacos , Piperazinas/toxicidade , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D4 , Proteínas Recombinantes/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of novel 1H-pyrazolo-[3,4-c]cyclophepta[1,2-c]thiophenes was prepared and screened at selected dopamine receptor subtypes. Compound 4 (NGB 4420) displayed high affinity and selectivity (>100-fold) for the D(4) over D(2) and other CNS receptors. This compound was identified as a D(4) antagonist via its attenuation of dopamine agonist-induced GTPgamma(35)S binding at D(4) receptor.
Assuntos
Receptores de Dopamina D2/metabolismo , Tiofenos/metabolismo , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Humanos , Ligantes , Ligação Proteica , Receptores de Dopamina D4 , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologiaRESUMO
The discovery, synthesis and structure-activity studies of a novel series of 2-arylpyrimidin-4-ones as CRF-1 receptor antagonists is described. These compounds are structurally simple and display appropriate physical properties for CNS agents