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1.
Proc Natl Acad Sci U S A ; 116(51): 26008-26019, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31796582

RESUMO

The transient receptor potential ankyrin 1 (TRPA1) channel functions as an irritant sensor and is a therapeutic target for treating pain, itch, and respiratory diseases. As a ligand-gated channel, TRPA1 can be activated by electrophilic compounds such as allyl isothiocyanate (AITC) through covalent modification or activated by noncovalent agonists through ligand binding. However, how covalent modification leads to channel opening and, importantly, how noncovalent binding activates TRPA1 are not well-understood. Here we report a class of piperidine carboxamides (PIPCs) as potent, noncovalent agonists of human TRPA1. Based on their species-specific effects on human and rat channels, we identified residues critical for channel activation; we then generated binding modes for TRPA1-PIPC interactions using structural modeling, molecular docking, and mutational analysis. We show that PIPCs bind to a hydrophobic site located at the interface of the pore helix 1 (PH1) and S5 and S6 transmembrane segments. Interestingly, this binding site overlaps with that of known allosteric modulators, such as A-967079 and propofol. Similar binding sites, involving π-helix rearrangements on S6, have been recently reported for other TRP channels, suggesting an evolutionarily conserved mechanism. Finally, we show that for PIPC analogs, predictions from computational modeling are consistent with experimental structure-activity studies, thereby suggesting strategies for rational drug design.


Assuntos
Simulação de Acoplamento Molecular , Piperidinas/farmacologia , Canal de Cátion TRPA1/química , Canal de Cátion TRPA1/efeitos dos fármacos , Animais , Sítios de Ligação , Canais de Cálcio/química , Canais de Cálcio/metabolismo , Desenho de Fármacos , Humanos , Isotiocianatos , Ligantes , Modelos Estruturais , Mutagênese , Oximas/farmacologia , Propofol/farmacologia , Domínios Proteicos , Ratos , Especificidade da Espécie , Canal de Cátion TRPA1/metabolismo
2.
J Psychopharmacol ; 34(1): 93-102, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31766938

RESUMO

PURPOSE: There is considerable interest in positive allosteric modulators (PAMs) of the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) subtype of ionotropic glutamate receptors as therapeutic agents for a range of cognitive and mood disorders. However, the challenge is to increase AMPA receptor (AMPAR) function sufficient to enhance cognitive function but not to the extent that there are mechanism-related pro-convulsant or convulsant side effects. In this present study, we report the preclinical pharmacology data for MDI-222, an AMPAR PAM which enhances cognition but has a much reduced side-effect (i.e. convulsant) liability relative to other molecules of this mechanism. METHODS: The pharmacological effects of MDI-222 were characterised in in vitro and in vivo preclinical electrophysiology, efficacy (cognition), side-effect (pro-convulsant/convulsant), tolerability and toxicity assays. RESULTS: We demonstrate that MDI-222 is an AMPAR PAM, since it enhanced AMPAR function in vitro at human (hGluA1-4) and rat (rGluA2) homomeric receptors, and potentiated hetero-oligomeric AMPARs in rat neurons. MDI-222 enhanced electrically evoked AMPAR-mediated synaptic transmission in the anaesthetised rat at 10 mg/kg (administered intravenously) and did not significantly lower the seizure threshold in the pro-convulsant maximal electroshock threshold test (MEST) at any dose tested up to a maximum of 30 mg/kg (administered by oral gavage (p.o.)). MDI-222 reversed a delay-induced deficit in novel object recognition (NOR) in rats with a minimum effective dose (MED) of 0.3 mg/kg (p.o.) following acute administration, which was reduced to 0.1 mg/kg following sub-chronic administration, and improved passive avoidance performance in scopolamine-impaired rats with a MED of 10 mg/kg p.o. On the other hand, MDI-222 was not pro-convulsant in the MEST, resulting in a therapeutic window between plasma concentrations that enhanced cognitive performance and those associated with mechanism-related side effects of ⩾1000-fold. Unfortunately, despite the excellent preclinical profile of this compound, further development had to be halted due to non-mechanism-related issues. CONCLUSIONS: We conclude that MDI-222 is an AMPAR PAM which enhances cognitive performance in rats and has a significantly improved safety profile in preclinical species.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Nootrópicos/efeitos adversos , Nootrópicos/farmacologia , Pirrolidinas/efeitos adversos , Pirrolidinas/farmacologia , Receptores de AMPA/fisiologia , Animais , Relação Dose-Resposta a Droga , Eletrochoque/estatística & dados numéricos , Humanos , Ratos , Convulsões/induzido quimicamente , Transmissão Sináptica/fisiologia
3.
J Med Chem ; 62(8): 4091-4109, 2019 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-30943032

RESUMO

Using structure- and ligand-based design principles, a novel series of piperidyl chromane arylsulfonamide Nav1.7 inhibitors was discovered. Early optimization focused on improvement of potency through refinement of the low energy ligand conformation and mitigation of high in vivo clearance. An in vitro hepatotoxicity hazard was identified and resolved through optimization of lipophilicity and lipophilic ligand efficiency to arrive at GNE-616 (24), a highly potent, metabolically stable, subtype selective inhibitor of Nav1.7. Compound 24 showed a robust PK/PD response in a Nav1.7-dependent mouse model, and site-directed mutagenesis was used to identify residues critical for the isoform selectivity profile of 24.


Assuntos
Canal de Sódio Disparado por Voltagem NAV1.7/química , Sulfonamidas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Analgésicos/química , Analgésicos/metabolismo , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Dor Crônica/tratamento farmacológico , Dor Crônica/patologia , Cães , Meia-Vida , Humanos , Ligantes , Masculino , Camundongos , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Ratos , Relação Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Bloqueadores do Canal de Sódio Disparado por Voltagem/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico
4.
J Med Chem ; 54(1): 78-94, 2011 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-21128618

RESUMO

A novel series of AMPAR positive modulators is described that were identified by high throughput screening. The molecules of the series have been optimized from a high quality starting point hit to afford excellent developability, tolerability, and efficacy profiles, leading to identification of a clinical candidate. Unusually for an ion channel target, this optimization was integrated with regular generation of ligand-bound crystal structures and uncovered a novel chemotype with a unique and highly conserved mode of interaction via a trifluoromethyl group.


Assuntos
Indazóis/síntese química , Receptores de AMPA/fisiologia , Regulação Alostérica , Animais , Cálcio/metabolismo , Cristalografia por Raios X , Cães , Ensaios de Triagem em Larga Escala , Humanos , Técnicas In Vitro , Indazóis/farmacocinética , Indazóis/farmacologia , Ligantes , Macaca fascicularis , Masculino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Conformação Molecular , Técnicas de Patch-Clamp , Multimerização Proteica , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/química , Proteínas Recombinantes/química , Solubilidade , Relação Estrutura-Atividade , Suínos , Porco Miniatura
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