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1.
ACS Med Chem Lett ; 15(2): 302-309, 2024 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-38352850

RESUMEN

Herein, we report the synthesis and characterization of a novel set of substituted indazole-ethanamines and indazole-tetrahydropyridines as potent serotonin receptor subtype 2 (5-HT2) agonists. Specifically, we examine the 5-HT2 pharmacology of the direct indazole analogs of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and related serotonergic tryptamines, and highlight the need for rigorous characterization of 5-HT2 subtype selectivity for these analogs, particularly for the 5-HT2B receptor subtype. Within this series, the potent analog VU6067416 (19d) was optimized to have suitable preclinical pharmacokinetic properties for in vivo dosing, although potent 5-HT2B agonist activity precluded further characterization for this series. Additionally, in silico docking studies suggest that the high potency of 19d may be a consequence of a halogen-bonding interaction with Phe2345.38 in the 5-HT2A orthosteric pocket.

2.
J Clin Invest ; 133(19)2023 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-37561580

RESUMEN

Negative regulation of exocytosis from secretory cells is accomplished through inhibitory signals from Gi/o GPCRs by Gßγ subunit inhibition of 2 mechanisms: decreased calcium entry and direct interaction of Gßγ with soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE) plasma membrane fusion machinery. Previously, we disabled the second mechanism with a SNAP25 truncation (SNAP25Δ3) that decreased Gßγ affinity for the SNARE complex, leaving exocytotic fusion and modulation of calcium entry intact and removing GPCR-Gßγ inhibition of SNARE-mediated exocytosis. Here, we report substantial metabolic benefit in mice carrying this mutation. Snap25Δ3/Δ3 mice exhibited enhanced insulin sensitivity and beiging of white fat. Metabolic protection was amplified in Snap25Δ3/Δ3 mice challenged with a high-fat diet. Glucose homeostasis, whole-body insulin action, and insulin-mediated glucose uptake into white adipose tissue were improved along with resistance to diet-induced obesity. Metabolic protection in Snap25Δ3/Δ3 mice occurred without compromising the physiological response to fasting or cold. All metabolic phenotypes were reversed at thermoneutrality, suggesting that basal autonomic activity was required. Direct electrode stimulation of sympathetic neuron exocytosis from Snap25Δ3/Δ3 inguinal adipose depots resulted in enhanced and prolonged norepinephrine release. Thus, the Gßγ-SNARE interaction represents a cellular mechanism that deserves further exploration as an additional avenue for combating metabolic disease.


Asunto(s)
Subunidades beta de la Proteína de Unión al GTP , Subunidades gamma de la Proteína de Unión al GTP , Insulinas , Ratones , Animales , Calcio/metabolismo , Subunidades beta de la Proteína de Unión al GTP/genética , Subunidades beta de la Proteína de Unión al GTP/metabolismo , Subunidades gamma de la Proteína de Unión al GTP/genética , Subunidades gamma de la Proteína de Unión al GTP/metabolismo , Exocitosis/fisiología , Proteínas SNARE/genética , Dieta , Obesidad/genética , Adipocitos/metabolismo , Insulinas/metabolismo , Insulina/metabolismo
3.
Eur J Neurosci ; 52(1): 2815-2826, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32449556

RESUMEN

Behavioral assays in the mouse can show marked differences between male and female animals of a given genotype. These differences identified in such preclinical studies may have important clinical implications. We recently made a mouse model with impaired presynaptic inhibition through Gßγ-SNARE signaling. Here, we examine the role of sexual dimorphism in the severity of the phenotypes of this model, the SNAP25Δ3 mouse. In males, we already reported that SNAP25Δ3 homozygotes demonstrated phenotypes in motor coordination, nociception, spatial memory and stress processing. We now report that while minimal sexually dimorphic effects were observed for the nociceptive, motor or memory phenotypes, large differences were observed in the stress-induced hyperthermia paradigm, with male SNAP25Δ3 homozygotes exhibiting an increase in body temperature subsequent to handling relative to wild-type littermates, while no such genotype-dependent effect was observed in females. This suggests sexually dimorphic mechanisms of Gßγ-SNARE signaling for stress processing or thermoregulation within the mouse. Second, we examined the effects of heterozygosity with respect to the SNAP25Δ3 mutation. Heterozygote SNAP25Δ3 animals were tested alongside homozygote and wild-type littermates in all of the aforementioned paradigms and displayed phenotypes similar to wild-type animals or an intermediate state. From this, we conclude that the SNAP25Δ3 mutation does not behave in an autosomal dominant manner, but rather displays incomplete dominance for many phenotypes.


Asunto(s)
Hipertermia , Caracteres Sexuales , Animales , Modelos Animales de Enfermedad , Exocitosis , Femenino , Masculino , Ratones , Memoria Espacial
4.
Sci Signal ; 12(569)2019 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-30783011

RESUMEN

G protein-coupled receptors (GPCRs) that couple to Gi/o proteins modulate neurotransmission presynaptically by inhibiting exocytosis. Release of Gßγ subunits from activated G proteins decreases the activity of voltage-gated Ca2+ channels (VGCCs), decreasing excitability. A less understood Gßγ-mediated mechanism downstream of Ca2+ entry is the binding of Gßγ to SNARE complexes, which facilitate the fusion of vesicles with the cell plasma membrane in exocytosis. Here, we generated mice expressing a form of the SNARE protein SNAP25 with premature truncation of the C terminus and that were therefore partially deficient in this interaction. SNAP25Δ3 homozygote mice exhibited normal presynaptic inhibition by GABAB receptors, which inhibit VGCCs, but defective presynaptic inhibition by receptors that work directly on the SNARE complex, such as 5-hydroxytryptamine (serotonin) 5-HT1b receptors and adrenergic α2a receptors. Simultaneously stimulating receptors that act through both mechanisms showed synergistic inhibitory effects. SNAP25Δ3 homozygote mice had various behavioral phenotypes, including increased stress-induced hyperthermia, defective spatial learning, impaired gait, and supraspinal nociception. These data suggest that the inhibition of exocytosis by Gi/o-coupled GPCRs through the Gßγ-SNARE interaction is a crucial component of numerous physiological and behavioral processes.


Asunto(s)
Subunidades beta de la Proteína de Unión al GTP/metabolismo , Subunidades gamma de la Proteína de Unión al GTP/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Proteína 25 Asociada a Sinaptosomas/metabolismo , Animales , Calcio , Exocitosis/fisiología , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Noqueados , Inhibición Neural/fisiología , Fenotipo , Unión Proteica , Transmisión Sináptica/fisiología , Proteína 25 Asociada a Sinaptosomas/genética
5.
J Med Chem ; 62(1): 342-358, 2019 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-30247901

RESUMEN

This work describes the discovery and characterization of novel 6-(1 H-pyrazolo[4,3- b]pyridin-3-yl)amino-benzo[ d]isothiazole-3-carboxamides as mGlu4 PAMs. This scaffold provides improved metabolic clearance and CYP1A2 profiles compared to previously discovered mGlu4 PAMs. From this work, 27o (VU6001376) was identified as a potent (EC50 = 50.1 nM, 50.5% GluMax) and selective mGlu4 PAM with an excellent rat DMPK profile ( in vivo rat CLp = 3.1 mL/min/kg, t1/2 = 445 min, CYP1A2 IC50 > 30 µM). Compound 27o was also active in reversing haloperidol induced catalepsy in a rodent preclinical model of Parkinson's disease.


Asunto(s)
Amidas/química , Receptores de Glutamato Metabotrópico/química , Regulación Alostérica , Amidas/metabolismo , Amidas/farmacocinética , Amidas/uso terapéutico , Animales , Encéfalo/metabolismo , Catalepsia/inducido químicamente , Catalepsia/tratamiento farmacológico , Catalepsia/patología , Citocromo P-450 CYP1A2/metabolismo , Semivida , Haloperidol/toxicidad , Humanos , Isoxazoles/química , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-Actividad
6.
Bioorg Med Chem Lett ; 27(21): 4858-4866, 2017 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-28958625

RESUMEN

Based on a hypothesis that an intramolecular hydrogen bond was present in our lead series of picolinamide mGlu5 NAMs, we reasoned that an inactive nicotinamide series could be modified through introduction of a fused heterocyclic core to generate potent mGlu5 NAMs. In this Letter, we describe the synthesis and evaluation of compounds that demonstrate the viability of that approach. Selected analogs were profiled in a variety of in vitro assays, and two compounds were evaluated in rat pharmacokinetic studies and a mouse model of obsessive-compulsive disorder. Ancillary pharmacology screening revealed that members of this series exhibited moderate inhibition of the dopamine transporter (DAT), and SAR was developed that expanded the selectivity for mGlu5 versus DAT.


Asunto(s)
Amidas/química , Receptor del Glutamato Metabotropico 5/metabolismo , Regulación Alostérica , Amidas/farmacocinética , Amidas/farmacología , Animales , Permeabilidad de la Membrana Celular/efectos de los fármacos , Perros , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Concentración 50 Inhibidora , Células de Riñón Canino Madin Darby , Ratones , Microsomas Hepáticos/metabolismo , Piridinas/química , Ratas , Receptor del Glutamato Metabotropico 5/química , Relación Estructura-Actividad , Triazoles/química
7.
J Med Chem ; 60(12): 5072-5085, 2017 06 22.
Artículo en Inglés | MEDLINE | ID: mdl-28530802

RESUMEN

Preclinical evidence in support of the potential utility of mGlu5 NAMs for the treatment of a variety of psychiatric and neurodegenerative disorders is extensive, and multiple such molecules have entered clinical trials. Despite some promising results from clinical studies, no small molecule mGlu5 NAM has yet to reach market. Here we present the discovery and evaluation of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (27, VU0424238), a compound selected for clinical evaluation. Compound 27 is more than 900-fold selective for mGlu5 versus the other mGlu receptors, and binding studies established a Ki value of 4.4 nM at a known allosteric binding site. Compound 27 had a clearance of 19.3 and 15.5 mL/min/kg in rats and cynomolgus monkeys, respectively. Imaging studies using a known mGlu5 PET ligand demonstrated 50% receptor occupancy at an oral dose of 0.8 mg/kg in rats and an intravenous dose of 0.06 mg/kg in baboons.


Asunto(s)
Aminopiridinas/farmacología , Evaluación Preclínica de Medicamentos/métodos , Ácidos Picolínicos/farmacología , Receptor del Glutamato Metabotropico 5/metabolismo , Relación Estructura-Actividad , Regulación Alostérica , Aminopiridinas/síntesis química , Animales , Técnicas de Química Sintética , Células HEK293 , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Macaca fascicularis , Masculino , Ratones Endogámicos , Ácidos Picolínicos/síntesis química , Ratas Sprague-Dawley , Receptor del Glutamato Metabotropico 5/agonistas , Distribución Tisular
8.
ACS Chem Neurosci ; 7(9): 1201-11, 2016 09 21.
Artículo en Inglés | MEDLINE | ID: mdl-27441572

RESUMEN

Metabotropic glutamate receptor 4 (mGlu4) is emerging as a potential therapeutic target for numerous central nervous system indications, including Parkinson's disease (PD). As the glutamate binding sites among the eight mGlu receptors are highly conserved, modulation of receptor activity via allosteric sites within the receptor transmembrane domains using positive and negative allosteric modulators (PAMs and NAMs, respectively) has become a common strategy. We and others have used PAMs targeting mGlu4 to show that potentiation of receptor signaling induces antiparkinsonian activity in a variety of PD animal models, including haloperidol-induced catalepsy and 6-hydroxydopamine-induced lesion. Recently, mGlu4 has been reported to form heteromeric complexes with other mGlu receptor subtypes, such as mGlu2, and the resulting heteromer exhibits a distinct pharmacological profile in response to allosteric modulators. For example, some mGlu4 PAMs do not appear to potentiate glutamate activity when mGlu2 and mGlu4 are coexpressed, whereas other compounds potentiate mGlu4 responses regardless of mGlu2 coexpression. We report here the discovery and characterization of VU0418506, a novel mGlu4 PAM with activity in rodent PD models. Using pharmacological approaches and Complemented Donor-Acceptor resonance energy transfer (CODA-RET) technology, we find that VU0418506 does not potentiate agonist-induced activity when mGlu2 and mGlu4 are heterodimerized, suggesting that the antiparkinsonian action of mGlu4 PAMs can be induced by compounds without activity at mGlu2/4 heteromers.


Asunto(s)
Antiparkinsonianos/síntesis química , Antiparkinsonianos/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Receptores de Glutamato Metabotrópico/metabolismo , Regulación Alostérica/efectos de los fármacos , Animales , Antiparkinsonianos/química , Antipsicóticos/farmacología , Apomorfina/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Catalepsia/inducido químicamente , Catalepsia/tratamiento farmacológico , Modelos Animales de Enfermedad , Agonistas de Dopamina/farmacología , Miembro Anterior/efectos de los fármacos , Miembro Anterior/fisiopatología , Ácido Glutámico/farmacología , Células HEK293 , Haloperidol/farmacología , Humanos , Oxidopamina/toxicidad , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/patología , Ratas , Ratas Sprague-Dawley , Receptores de Glutamato Metabotrópico/genética , Transfección
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