RESUMO
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
Metabotropic glutamate receptor subtype 5 (mGluR5) is a potential drug target in neurological and psychiatric disorders, and subtype-selective allosteric modulators have attracted much attention as potential drug candidates. In this study, the binding sites of three novel 2-methyl-6-(phenylethynyl)pyridine (MPEP)-derived negative allosteric modulators, 2-, 3-, and 4-BisPEB, have been characterized. 2-, 3-, and 4-BisPEB are 1,3-bis(pyridinylethynyl)-benzenes and differ only by the position of the nitrogen atoms in the pyridine rings. Despite their high structural similarity, 2-BisPEB [1,3-bis(pyridin-2-ylethynyl)-benzene, nitrogen atoms in ortho positions], with an IC(50) value in the nanomolar range, is significantly more potent than the 3- and 4-pyridyl analogs. Mutational analysis, directed by a previously published mGluR5 homology model, was used to determine key residues for the ligand-receptor interactions that may explain the potency differences of 2-, 3-, and 4-BisPEB. Residues Ile651, Pro655, Tyr659, Asn747, Trp785, Phe788, Tyr792, Ser809, and Ala810 were found to have critical roles for the activity of one or more of the three BisPEBs and the reference compound MPEP. The mutagenesis data suggest that the higher potency of 2-BisPEB is due to hydrogen bonding to Ser809 because the S809A mutation made 2-BisPEB equipotent to 3- and 4-BisPEB (IC(50), 1-2.5 µM). The potency of MPEP was also greatly affected by S809A (52-fold), suggesting that a Ser809-mediated hydrogen bond is also a key interaction between MPEP and mGluR5. Potential binding modes of 2-, 3-, and 4-BisPEB obtained by molecular docking to the mGluR5 homology model provide a structural context for the reported major mutational effects.
Assuntos
Alcinos/síntese química , Derivados de Benzeno/química , Colinérgicos/química , Simulação de Acoplamento Molecular , Piridinas/química , Receptores de Glutamato Metabotrópico/metabolismo , Alcinos/farmacologia , Regulação Alostérica , Animais , Derivados de Benzeno/farmacologia , Sítios de Ligação , Cálcio/metabolismo , Linhagem Celular , Colinérgicos/farmacologia , Cricetinae , Humanos , Ligação de Hidrogênio , Mutação Puntual , Piridinas/farmacologia , Ensaio Radioligante , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/genética , Relação Estrutura-AtividadeRESUMO
4-(1-Phenyl-1H-pyrazol-4-yl)quinoline (1) was identified by screening the Lundbeck compound collection, and characterized as having mGlu4 receptor positive allosteric modulator properties. Compound 1 is selective over other mGlu receptors and a panel of GPCRs, ion channels and enzymes, but has suboptimal lipophilicity and high plasma and brain non-specific binding. In view of the challenges at the hit-to-lead stage previously reported in the development of mGlu4 receptor positive allosteric modulators (PAMs), a thorough structure-mGlu4 PAM activity relationship study was conducted to interrogate the chemical tractability of this chemotype. The central pyrazole ring tolerates the addition of one or two methyl groups. The C-7 position of the quinoline ring provides a site tolerant to hydrophilic substituents, enabling the design of diverse analogs with good in vitro mGlu4 PAM potency and efficacy, as well as improved microsomal turnover in vitro, compared to 1. In spite of the excellent ligand efficiency of 1 (LE=0.43), optimization of in vitro potency for this series reached a plateau around EC(50)=200 nM.
Assuntos
Regulação Alostérica , Quinolinas/farmacologia , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Ratos , Relação Estrutura-AtividadeRESUMO
A series of 6-aryl-3-pyrrolidinylpyridine analogs was explored as structurally novel negative allosteric modulators of the mGlu5 receptor lacking an alkyne or oxadiazole moiety. Compounds in this series were characterized by tractable SAR, good in vitro potencies and brain penetration in rodents.
Assuntos
Piridinas/farmacologia , Pirrolidinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Pirrolidinas/síntese química , Pirrolidinas/química , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/sangue , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Synthesis, SAR and physico-chemical properties of an alkyl aminothiazole series 8 and 16 are described. 2-Pyridylaminothiazole based compounds such as 8c and 16a exhibit high affinity at the NPY(5) receptor with desirable cLogPs and solubilities. However, they also suffer from high in vitro and in vivo clearance. Compound 16a partially inhibits the feeding behavior elicited by i.c.v. injection of the selective NPY(5) agonist [cPP(1-7), NPY(19-23), Ala(31), Aib(32), Gln(34)]-human pancreatic polypeptide polypeptide (cPP).
Assuntos
Receptores de Neuropeptídeo Y/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Comportamento Alimentar/efeitos dos fármacos , Humanos , Injeções Intraventriculares , Ratos , Solubilidade , Sulfonamidas/administração & dosagem , Sulfonamidas/químicaRESUMO
A series of 3-imino-2-indolones are the first published, high-affinity antagonists of the galanin GAL3 receptor. One example, 1,3-dihydro-1-phenyl-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one (9), was shown to have high affinity for the human GAL3 receptor (Ki=17 nM) and to be highly selective for GAL3 over a broad panel of targets, including GAL1 and GAL2. Compound 9 was also shown to be an antagonist in a human GAL3 receptor functional assay (Kb=29 nM).
Assuntos
Iminas/síntese química , Indóis/síntese química , Receptor Tipo 3 de Galanina/antagonistas & inibidores , Animais , Ligação Competitiva , Encéfalo/metabolismo , Células COS , Chlorocebus aethiops , AMP Cíclico/biossíntese , Humanos , Iminas/farmacocinética , Iminas/farmacologia , Indóis/farmacocinética , Indóis/farmacologia , Ligantes , Ensaio Radioligante , Ratos , Receptor Tipo 1 de Galanina/efeitos dos fármacos , Receptor Tipo 2 de Galanina/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Group III metabotropic glutamate (mGlu) receptors are localized in presynaptic terminals within basal ganglia (BG) circuitry that become hyperactive due to dopamine depletion in Parkinson's disease (PD). For this reason, group III mGlu receptors, in particular mGlu4, have been considered as key strategic targets for non-dopaminergic pharmacological treatments aimed at modulating these synapses, without producing the well known side-effects of l-DOPA, in particular the highly disabling l-DOPA-induced dyskinesia (LID). Herein we add physiological and functional support to this hypothesis using Lu AF21934, a novel selective and brain-penetrant mGlu4 receptor positive allosteric modulator (PAM) tool compound. By in vitro electrophysiological recordings we demonstrate that Lu AF21934 inhibits corticostriatal synaptic transmission and enhances the effect of the orthosteric mGlu4 receptor-preferred agonist LSP1-2111. In naïve rats, Lu AF21934 dose-dependently (10 and 30 mg/kg) alleviated haloperidol-induced catalepsy. In hemiparkinsonian rats (unilateral 6-hydroxydopamine lesion of the substantia nigra pars compacta), Lu AF21934 alone did not affect akinesia at the doses tested (10 and 30 mg/kg). However, when Lu AF21934 was combined with sub-threshold doses of l-DOPA (1 and 5 mg/kg), it acted synergistically in alleviating akinesia in a dose-dependent manner and, notably, also reduced the incidence of LID but not its severity. Interestingly, these effects occurred at Lu AF21934 brain free concentrations that showed functional activity in in vitro screens (calcium flux and electrophysiology assays). These results support the potential for antiparkinsonian clinical use of a combined treatment consisting in l-DOPA and a mGlu4 receptor PAM to reduce efficacious l-DOPA doses (generally known as l-DOPA sparing), while maintaining the same benefit on PD motor troubles, and at the same time minimizing the development of LID. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
Assuntos
Regulação Alostérica/fisiologia , Anilidas/farmacologia , Ácidos Cicloexanocarboxílicos/farmacologia , Discinesia Induzida por Medicamentos/tratamento farmacológico , Agonistas de Aminoácidos Excitatórios/farmacologia , Levodopa/farmacologia , Doença de Parkinson/tratamento farmacológico , Receptores de Glutamato Metabotrópico/agonistas , Regulação Alostérica/efeitos dos fármacos , Aminobutiratos/agonistas , Aminobutiratos/farmacologia , Aminobutiratos/uso terapêutico , Anilidas/farmacocinética , Anilidas/uso terapêutico , Animais , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Ácidos Cicloexanocarboxílicos/farmacocinética , Ácidos Cicloexanocarboxílicos/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Agonistas de Aminoácidos Excitatórios/farmacocinética , Agonistas de Aminoácidos Excitatórios/uso terapêutico , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Haloperidol/antagonistas & inibidores , Haloperidol/farmacologia , Levodopa/efeitos adversos , Levodopa/uso terapêutico , Masculino , Oxidopamina , Ácidos Fosfínicos/agonistas , Ácidos Fosfínicos/farmacologia , Ácidos Fosfínicos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Receptores de Glutamato Metabotrópico/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologiaRESUMO
A series of compounds based on the mGluR5-selective ligand 2-methyl-6-(phenylethynyl)pyridine (MPEP) were designed and synthesized. The compounds were found to be either structural analogues of MPEP, substituted monomers, or dimeric analogues. All compounds retained mGluR5 selectivity with only weak or no activity at other mGluRs or iGluRs. The substituted analogue, 1,3-bis(pyridin-2-ylethynyl)benzene (19), is a potent negative modulator at mGluR5, whereas all other compounds lost potency relative to MPEP and showed that activity is highly dependent on the position of the nitrogen atom in the pyridine moieties. A homology modeling and ligand docking study was used to understand the binding mode and the observed selectivity of compound 19.
Assuntos
Alcinos/síntese química , Ansiolíticos/síntese química , Transtornos de Ansiedade/tratamento farmacológico , Piridinas/síntese química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Alcinos/farmacologia , Alcinos/uso terapêutico , Regulação Alostérica , Sequência de Aminoácidos , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Transtornos de Ansiedade/metabolismo , Sítios de Ligação , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Cricetinae , Dimerização , Ácido Glutâmico/metabolismo , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Ligação Proteica , Piridinas/farmacologia , Piridinas/uso terapêutico , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of amino analogs of 1,3-dihydro-1-phenyl-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one (1) were synthesized to improve aqueous solubility, while retaining high affinity for the human galanin Gal3 receptor. A very potent analog (9e, 1,3-dihydro-1-[3-(2-pyrrolidinylethoxy)phenyl]-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one, Ki=5 nM) shows good selectivity and solubility of 48 microg/mL at pH 7.4.