RESUMEN
There is preclinical evidence supporting the finding that the GABA(B) receptor orthosteric agonist, baclofen, has significant effects on eating behavior suggesting the potential therapeutic application of this compound for the treatment of eating related disorders. However, the wide clinical use of baclofen might be limited by the appearance of sedative and motor impairment effects. The identification of positive allosteric modulators (PAMs) of GABA(B) receptors represents a novel therapeutic approach to reduce the centrally-mediated adverse effects typical of the GABA(B) receptor orthosteric agonist. In the present work, we report the in vitro profile of a novel chemical structure, 2-{1-[2-(4-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]-2-piperidinyl}ethanol (CMPPE) identified by screening the GSK compound collection. CMPPE potentiates GABA-stimulated [(35)S]GTPγS binding to membranes of human recombinant cell line and of rat brain cortex. GABA concentration-response curves (CRC) in the presence of fixed concentrations of CMPPE, in rat native tissue, revealed an increase of both the potency and maximal efficacy of GABA. A similar modulatory effect was observed in GABA(B) receptor-mediated activation of inwardly rectifying potassium channels in hippocampal neurons. CMPPE (30-100 mg/kg) and GS39783 (100 mg/kg) significantly decreased food consumption in rat without impairment on the animal locomotor activity. On the contrary, baclofen (2.5 mg/kg) decreased both food intake and motor performance. All together these findings confirm the role of GABA(B) system in controlling animal food intake and for the first time demonstrate that GABA(B) receptor PAMs may represent a novel pharmacological approach to treat eating disorders without unwanted sedative effects.
Asunto(s)
Baclofeno/farmacología , Ciclopentanos/farmacología , Agonistas de Receptores GABA-B/farmacología , Terapia Molecular Dirigida , Pirazoles/farmacología , Pirimidinas/farmacología , Receptores de GABA-B/metabolismo , Animales , Encéfalo/metabolismo , Células CHO , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Cricetinae , Evaluación Preclínica de Medicamentos , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Fenómenos Electrofisiológicos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Masculino , Proteínas de la Membrana/análisis , Actividad Motora/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Pirazoles/química , Pirimidinas/química , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de GABA-B/efectos de los fármacos , Receptores de GABA-B/genética , Transfección , Ácido gamma-Aminobutírico/fisiologíaAsunto(s)
Dibenzocicloheptenos/síntesis química , Dibenzocicloheptenos/farmacología , Hipnóticos y Sedantes/síntesis química , Ciclización , Dibenzocicloheptenos/química , Humanos , Hipnóticos y Sedantes/química , Hipnóticos y Sedantes/farmacología , Mianserina/análogos & derivados , Mianserina/química , Mianserina/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
Histamine H(1) and serotonin 5-HT(2A) receptors mediate two different mechanisms involved in sleep regulation: H(1) antagonists are sleep inducers, while 5-HT(2A) antagonists are sleep maintainers. Starting from 9'a, a novel spirotetracyclic compound endowed with good H(1)/5-HT(2A) potency but poor selectivity, very high Cli, and a poor P450 profile, a specific optimization strategy was set up. In particular, we investigated the possibility of introducing appropriate amino acid moieties to optimize the developability profile of the series. Following this zwitterionic approach, we were able to identify several advanced leads (51, 65, and 73) with potent dual H(1)/5-HT(2A) activity and appropriate developability profiles. These compounds exhibited efficacy as hypnotic agents in a rat telemetric sleep model with minimal effective doses in the range 3-10 mg/kg po.
Asunto(s)
Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Antagonistas de los Receptores Histamínicos H1/síntesis química , Hipnóticos y Sedantes/síntesis química , Receptor de Serotonina 5-HT2A/metabolismo , Antagonistas del Receptor de Serotonina 5-HT2/síntesis química , Sueño/efectos de los fármacos , Compuestos de Espiro/síntesis química , Animales , Disponibilidad Biológica , Encéfalo/metabolismo , Línea Celular , Corteza Cerebral/metabolismo , Cricetinae , Cricetulus , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Antagonistas de los Receptores Histamínicos H1/química , Antagonistas de los Receptores Histamínicos H1/farmacología , Humanos , Hipnóticos y Sedantes/química , Hipnóticos y Sedantes/farmacología , Masculino , Microsomas Hepáticos/metabolismo , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Antagonistas del Receptor de Serotonina 5-HT2/química , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
5-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones and 3,4-dihydro-2(1H)-quinolinones have been identified with different combinations of 5-HT(1) autoreceptor antagonist and hSerT potencies and excellent rat PK profiles. The availability of tool compounds with a range of profiles at targets known to play a key role in the control of synaptic 5-HT levels will allow exploration of different pharmacological profiles in a range of animal behavioral and disease models.
Asunto(s)
Quinolonas/química , Receptores de Serotonina 5-HT1/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Animales , Autorreceptores/antagonistas & inhibidores , Autorreceptores/efectos de los fármacos , Quinolonas/farmacocinética , Ratas , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Sinapsis/químicaRESUMEN
A novel imidazobenzazepine template (5a) with potent dual H(1)/5-HT(2A) antagonist activity was identified. Application of a zwitterionic approach to this poorly selective and poorly developable starting point successfully delivered a class of high quality leads, 3-[4-(3-R(1)-2-R-5H-imidazo[1,2-b][2]benzazepin-11-yl)-1-piperazinyl]-2,2-dimethylpropanoic acids (e.g., 9, 19, 20, and 21), characterized by potent and balanced H(1)/5-HT(2A) receptor antagonist activities and good developability profiles.
Asunto(s)
Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Antagonistas de la Serotonina/uso terapéutico , Trastornos del Sueño-Vigilia/tratamiento farmacológico , HumanosRESUMEN
Bioisoteric replacement of the metabolically labile N-methyl amide group of a series of benzoxazinones with small heterocyclic rings has led to novel series of fused tricyclic benzoxazines which are potent 5-HT(1A/B/D) receptor antagonists with and without concomitant human serotonin transporter (hSerT) activity. Optimizing against multiple parameters in parallel identified 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide (GSK588045) as a potent 5-HT(1A/B/D) receptor antagonist with a high degree of selectivity over human ether-a-go-go related gene (hERG) potassium channels, favorable pharmacokinetics, and excellent activity in vivo in rodent pharmacodynamic (PD) models. On the basis of its outstanding overall profile, this compound was progressed as a clinical candidate with the ultimate aim to assess its potential as a faster acting antidepressant/anxiolytic with reduced side-effect burden.
Asunto(s)
Ansiolíticos/síntesis química , Antidepresivos/síntesis química , Benzoxazinas/síntesis química , Antagonistas del Receptor de Serotonina 5-HT1 , Animales , Ansiolíticos/farmacocinética , Ansiolíticos/farmacología , Antidepresivos/farmacocinética , Antidepresivos/farmacología , Benzoxazinas/farmacocinética , Benzoxazinas/farmacología , Callithrix , Línea Celular , Corteza Cerebral/metabolismo , Cricetinae , Cricetulus , Sistema Enzimático del Citocromo P-450/metabolismo , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/metabolismo , Cobayas , Humanos , Técnicas In Vitro , Masculino , Microsomas Hepáticos/metabolismo , Unión Proteica , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Relación Estructura-ActividadRESUMEN
8-[2-(4-Aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones have been identified as highly potent 5-HT(1A/B/D) receptor antagonists with and without additional SerT activity and a high degree of selectivity over hERG potassium channels. Modulation of the different target activities gave compounds with a range of profiles suitable for further in vivo characterization.