RESUMEN
Structure-activity studies of 4-substituted-2,5-dimethoxyphenethylamines led to the discovery of 2,5-dimethoxy-4-thiotrifluoromethylphenethylamines, including CYB210010, a potent and long-acting serotonin 5-HT2 receptor agonist. CYB210010 exhibited high agonist potency at 5-HT2A and 5-HT2C receptors, modest selectivity over 5-HT2B, 5-HT1A, 5-HT6, and adrenergic α2A receptors, and lacked activity at monoamine transporters and over 70 other proteins. CYB210010 (0.1-3 mg/kg) elicited a head-twitch response (HTR) and could be administered subchronically at threshold doses without behavioral tolerance. CYB210010 was orally bioavailable in three species, readily and preferentially crossed into the CNS, engaged frontal cortex 5-HT2A receptors, and increased the expression of genes involved in neuroplasticity in the frontal cortex. CYB210010 represents a new tool molecule for investigating the therapeutic potential of 5-HT2 receptor activation. In addition, several other compounds with high 5-HT2A receptor potency, yet with little or no HTR activity, were discovered, providing the groundwork for the development of nonpsychedelic 5-HT2A receptor ligands.
Asunto(s)
Fenetilaminas , Agonistas del Receptor de Serotonina 5-HT2 , Relación Estructura-Actividad , Animales , Humanos , Fenetilaminas/farmacología , Fenetilaminas/química , Fenetilaminas/síntesis química , Administración Oral , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Agonistas del Receptor de Serotonina 5-HT2/química , Agonistas del Receptor de Serotonina 5-HT2/síntesis química , Masculino , Disponibilidad Biológica , Ratas , Ratones , Ratas Sprague-Dawley , Descubrimiento de Drogas , Receptores de Serotonina 5-HT2/metabolismo , Receptor de Serotonina 5-HT2A/metabolismoRESUMEN
We define the pharmacological and pharmacokinetic profiles of a novel α(2C)-adrenoceptor agonist, compound A [N-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1,4-benzoxazin-6-yl]-N-ethyl-N'-methylurea]. This compound has high affinity (K(i)) for the human α(2C)-adrenoceptor (K(i) = 12 nM), and 190- to 260-fold selectivity over the α(2A)- and α(2B)-adrenoceptor subtypes. In cell-based functional assays, compound A produced good agonist (EC(50) = 166 nM) and efficacy (E(max) = 64%) responses at the α(2C)-adrenoceptor, much lower potency and efficacy at the α(2A)-adrenoceptor (EC(50) = 1525 nM; E(max) = 8%) and α(2B)-adrenoceptor (EC(50) = 5814 nM; E(max) = 21%) subtypes, and low or no affinity and functional activity at the α(1A)-, α(1B)-, and α(1D)-adrenoceptor subtypes. In the human saphenous vein postjunctional α(2C)-adrenoceptor bioassay, compound A functions as a potent agonist (pD(2) = 6.3). In a real-time contraction bioassay of pig nasal mucosa, compound A preferentially constricted the veins (EC(50) = 108 nM), and the magnitude of arteriolar contraction reached only 50% of the maximum venular responses. Compound A exhibited no effect on locomotor activity, sedation, and body temperature in mice (up to 100 mg/kg) and did not cause hypertension and mydriasis (30 mg/kg) in conscious rats. Compound A is orally bioavailable (24%) with good plasma exposure. This compound is a substrate for the efflux P-glycoprotein transporter, resulting in very low central nervous system (CNS) penetration. In summary, compound A is a highly selective, orally active, and non-CNS-penetrating α(2C)-adrenoceptor agonist with desirable in vitro and in vivo pharmacological properties suitable for the treatment of nasal congestion.
Asunto(s)
Agonistas Adrenérgicos/química , Agonistas Adrenérgicos/farmacología , Compuestos de Metilurea/química , Compuestos de Metilurea/farmacología , Morfolinas/química , Morfolinas/farmacología , Actividad Motora/efectos de los fármacos , Mucosa Nasal/efectos de los fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Vena Safena/efectos de los fármacos , Agonistas Adrenérgicos/metabolismo , Animales , Células CHO , Cricetinae , Cricetulus , Humanos , Masculino , Compuestos de Metilurea/metabolismo , Ratones , Ratones Endogámicos C57BL , Morfolinas/metabolismo , Actividad Motora/fisiología , Mucosa Nasal/metabolismo , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/metabolismo , Vena Safena/metabolismo , PorcinosRESUMEN
Modification of prototype NK(1) antagonist 2 resulted in the synthesis of a series of simple amides 6 and retroamides 9. These compounds were shown to be potent and orally active NK(1) antagonists.
Asunto(s)
Antagonistas del Receptor de Neuroquinina-1 , Piperidinas/síntesis química , Piperidinas/farmacología , Animales , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Gerbillinae , Semivida , Piperidinas/farmacocinética , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Analgesic properties of orthosteric agonists of the muscarinic M4 receptor subtype have been documented in literature reports, with evidence from pharmacological and in vivo receptor knock out (KO) studies. Constitutive M4 receptor KO mice demonstrated an increased response in the formalin pain model, supporting this hypothesis. Two novel positive allosteric modulators (PAM) of the M4 receptor, Compounds 1 and 2, were characterized in rodent models of acute nociception. Results indicated decreased time spent on nociceptive behaviors in the mouse formalin model, and efficacy in the mouse tail flick assay. The analgesic-like effects of Compounds 1 and 2 were shown to be on target, as the compounds lacked any activity in constitutive M4 KO mice, while retaining activity in wild type control littermates. The analgesic-like effects of Compounds 1 and 2 were significantly diminished in KO mice that have selective deletion of the M4 receptor in neurons that co-express the dopaminergic D1 receptor subtype, suggesting a centrally-mediated effect on nociception. The opioid antagonist naloxone did not diminish the effect of Compound 1, indicating the effects of Compound 1 are not secondarily linked to opioid pathways. Compound 1 was evaluated in the rat, where it demonstrated analgesic-like effects in tail flick and a subpopulation of spinal nociceptive sensitive neurons, suggesting some involvement of spinal mechanisms of nociceptive modulation. These studies indicate that M4 PAMs may be a tractable target for pain management assuming an appropriate safety profile, and it appears likely that both spinal and supraspinal pathways may mediate the antinociceptive-like effects.
Asunto(s)
Regulación Alostérica/efectos de los fármacos , Nocicepción/efectos de los fármacos , Receptor Muscarínico M4/agonistas , Regulación Alostérica/fisiología , Analgésicos/farmacología , Analgésicos Opioides/farmacología , Animales , Colinérgicos/farmacología , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Antagonistas de Narcóticos/farmacología , Nocicepción/fisiología , Dolor/metabolismo , Dolor/fisiopatología , Ratas , Ratas Sprague-Dawley , Receptor Muscarínico M4/efectos de los fármacos , Receptor Muscarínico M4/metabolismoRESUMEN
The adenosine A(2A) receptor has been implicated in the underlying biology of various neurological and psychiatric disorders, including Parkinson's disease (PD) and depression. Preladenant and SCH 412348 [7-[2-[4-2,4-difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] are potent competitive antagonists of the human A(2A) receptor (K(i) = 1.1 and 0.6 nM, respectively) and have >1000-fold selectivity over all other adenosine receptors, making these compounds the most selective A(2A) receptor antagonists reported to date. Both compounds attenuate hypolocomotion induced by the A(2A) receptor agonist CGS-21680 [2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine], suggesting that they inhibit A(2A) receptor activity in vivo. Their high degree of selectivity and robust in vivo activity make preladenant and SCH 412348 useful tools to investigate the role of the A(2A) receptor system in animal models of PD and depression. Oral administration of preladenant and SCH 412348 (0.1-1 mg/kg) to rats potentiated 3,4-dihydroxy-L-phenylalanine (L-Dopa)-induced contralateral rotations after 6-hydroxydopamine lesions in the medial forebrain bundle and potently attenuated the cataleptic effects of haloperidol. Preladenant (1 mg/kg) inhibited L-Dopa-induced behavioral sensitization after repeated daily administration, which suggests a reduced risk of the development of dyskinesias. Finally, preladenant and SCH 412348 exhibited antidepressant-like profiles in models of behavioral despair, namely the mouse tail suspension test and the mouse and rat forced swim test. These studies demonstrate that preladenant and SCH 412348 are potent and selective A(2A) receptor antagonists and provide further evidence of the potential therapeutic benefits of A(2A) receptor inhibition in PD (with reduced risk of dyskinesias) and depression (one of the primary nonmotor symptoms of PD).
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Trastorno Depresivo/tratamiento farmacológico , Modelos Animales de Enfermedad , Trastornos del Movimiento/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Pirimidinas/farmacología , Triazoles/farmacología , Animales , Células CHO , Cricetinae , Cricetulus , Trastorno Depresivo/metabolismo , Humanos , Masculino , Ratones , Trastornos del Movimiento/metabolismo , Fármacos Neuroprotectores/química , Pirimidinas/química , Ratas , Receptor de Adenosina A2A/metabolismo , Triazoles/químicaRESUMEN
A series of nortropane analogs based on previously reported compound 1 have been synthesized and shown to bind to the nociceptin receptor with high affinity. The synthesis and structure-activity relationships around the C-3 nortropane substitution are described. From the SAR study and hPXR screening effort, compound 15 was identified to possess potent oral antitussive and anxiolytic-like activities in the guinea pig models.
Asunto(s)
Ansiedad/tratamiento farmacológico , Química Farmacéutica/métodos , Tos/tratamiento farmacológico , Nortropanos/síntesis química , Receptores Opioides/metabolismo , Administración Oral , Animales , Ansiolíticos/farmacología , Antitusígenos/farmacología , Diseño de Fármacos , Cobayas , Cinética , Ligandos , Estructura Molecular , Nortropanos/farmacología , Receptores Opioides/química , Relación Estructura-Actividad , Receptor de NociceptinaRESUMEN
Antagonism of the adenosine A(2a) receptor offers great promise in the treatment of Parkinson's disease. In the course of exploring pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A(2A) antagonists, which led to clinical candidate SCH 420814, we prepared 1,2,4-triazolo[1,5-c]pyrimidines with potent and selective (vs A(1)) A(2a) antagonist activity, including oral activity in the rat haloperidol-induced catalepsy model. Structure-activity relationships and plasma levels are described for this series.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Enfermedad de Parkinson/tratamiento farmacológico , Pirimidinas/farmacología , Triazoles/síntesis química , Administración Oral , Animales , Área Bajo la Curva , Catalepsia , Química Farmacéutica/métodos , Diseño de Fármacos , Haloperidol/farmacología , Modelos Químicos , Pirimidinas/síntesis química , Pirimidinas/química , Ratas , Relación Estructura-Actividad , Triazoles/farmacologíaRESUMEN
The discovery of 1 as a high-affinity ligand for the nociceptin receptor has led to the synthesis of a series of tropane (8-methyl-8-azabicyclo[3.2.1]octane) derivatives as optimized ligands. These compounds exhibit high affinity for the nociceptin receptor, moderate to excellent selectivity over the opioid mu receptor, and behave as full agonists. In this Letter, we present the synthesis and highlight the structure-activity relationship of tropane derivatives culminating in the identification of 24 and 32 as potent and orally active antitussive and anxiolytic agents. The in vitro and in vivo activities, pharmacokinetic profile, and the hPXR activity, which predicts the potential 3A4 induction in human, are disclosed.
Asunto(s)
Ansiolíticos/síntesis química , Antitusígenos/síntesis química , Ansiedad/tratamiento farmacológico , Tos/tratamiento farmacológico , Ligandos , Tropanos/síntesis química , Animales , Ansiolíticos/farmacología , Antitusígenos/farmacología , Capsaicina/química , Química Farmacéutica/métodos , Diseño de Fármacos , Cobayas , Humanos , Receptor X de Pregnano , Receptores Opioides/química , Receptores de Esteroides/química , Relación Estructura-Actividad , Tropanos/farmacología , Receptor de NociceptinaRESUMEN
Vasopressin 1b (V1b) antagonists have been postulated as possible treatments for depression and anxiety. A novel series of potent and selective V1b antagonists has been identified starting from an in-house screen hit. The incorporation of a sulfonamide linker between a tetrahydroisoquinoline core and amino piperidine lead to the identification of a V1b antagonist with similar affinity for human and rat receptors. Further optimization of the right hand portion afforded potent V1b antagonists that possessed moderate to high selectivity over other receptors.
Asunto(s)
Fármacos Antidiuréticos/química , Antagonistas de los Receptores de Hormonas Antidiuréticas , Quinolinas/química , Sulfonamidas/química , Animales , Fármacos Antidiuréticos/síntesis química , Fármacos Antidiuréticos/farmacología , Humanos , Quinolinas/síntesis química , Quinolinas/farmacología , Ratas , Receptores de Oxitocina/antagonistas & inhibidores , Receptores de Oxitocina/metabolismo , Receptores de Vasopresinas/metabolismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacologíaRESUMEN
Orphanin FQ/nociceptin (OFQ/N) is the endogenously occurring peptide ligand for the nociceptin opioid receptor (NOP) that produces anxiolytic-like effects in mice and rats. The present study assessed the anxiolytic-like activity of 8-[bis(2-methylphenyl)-methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510), a novel potent piperidine NOP agonist (EC(50) = 12 nM) that binds with high affinity (K(i) = 0.3 nM) and functional selectivity (>50-fold over the mu-, kappa-, and delta-opioid receptors). The anxiolytic-like activity and side-effect profile of SCH 221510 were assessed in a variety of models and the benzodiazepine, chlordiazepoxide (CDP), was included for comparison. The effects of chronic dosing of SCH 221510 were also assessed. Furthermore, the specificity of the anxiolytic-like effect of SCH 221510 was investigated with the NOP receptor antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) and the opioid receptor antagonist naltrexone. Like CDP (1-30 mg/kg i.p.), SCH 221510 (1-30 mg/kg p.o.) produced anxiolytic-like effects in the elevated plus-maze (rat and gerbil), Vogel conflict (rat), conditioned lick suppression (rat), fear-potentiated startle (rat), and pup separation-induced vocalization (guinea pig) assays. In the Vogel conflict, the anxiolytic-like effect of SCH 221510 (10 mg/kg) was attenuated by J-113397 (3-10 mg/kg p.o.), but not naltrexone (3-30 mg/kg i.p.). Additionally, the anxiolytic-like effects of SCH 221510 did not change appreciably following 14-day b.i.d. dosing in rats (10 mg/kg). Furthermore, unlike CDP, SCH 221510 (3-30 mg/kg) produced anxiolytic-like activity at doses that did not disrupt overt behavior. Collectively, these data suggest that NOP agonists such as SCH 221510 may have an anxiolytic-like profile similar to benzodiazepines, with a reduced side-effect liability.
Asunto(s)
Ansiolíticos/farmacología , Compuestos de Azabiciclo/farmacología , Conducta Animal/efectos de los fármacos , Receptores Opioides/agonistas , Animales , Animales Recién Nacidos , Ansiolíticos/química , Compuestos de Azabiciclo/química , Bencimidazoles/farmacología , Células CHO , Cricetinae , Cricetulus , Femenino , Gerbillinae , Cobayas , Humanos , Masculino , Estructura Molecular , Antagonistas de Narcóticos , Piperidinas/farmacología , Unión Proteica , Ratas , Ratas Wistar , Receptores Opioides/metabolismo , Receptor de NociceptinaRESUMEN
RATIONALE: Adenosine and dopamine interact within the striatum to control striatopallidal output and globus pallidus GABA release. Manipulating striatal adenosine transmission via blockade of the A2A receptor subtype can compensate for the reduced dopamine activity within the striatum that underlies movement disorders such as antipsychotic-induced extrapyramidal syndrome (EPS) and Parkinson's disease (PD). Preclinical studies in the rat have demonstrated that adenosine A2A receptor antagonists can attenuate behaviors reflecting reduced dopamine activity, such as haloperidol-induced catalepsy and hypoactivity. OBJECTIVES: In the present studies using nonhuman primates, adenosine antagonists were tested against haloperidol-induced EPS in Cebus apella and haloperidol-induced catalepsy in Saimiri sciureus (squirrel monkey). Specifically, the A2A receptor antagonists, SCH 412348 (0.3-30 mg/kg PO) and KW-6002 (3-100 mg/kg PO); the A1/A2A receptor antagonist, caffeine (1-30 mg/kg PO and IM); and the A1 receptor antagonist, DPCPX (3-30 mg/kg PO) were tested in at least one of these models. RESULTS: SCH 412348 (10-30 mg/kg), KW-6002 (57-100 mg/kg), and caffeine (30 mg/kg) significantly increased the time to EPS onset. Additionally, SCH 412348, KW-6002, and caffeine afforded protection from the onset of EPS for at least 6 h in some of the primates. SCH 412348 (10 mg/kg) and caffeine (10 mg/kg) significantly reduced haloperidol-induced catalepsy. DPCPX produced a very slight attenuation of EPS at 30 mg/kg, but had no effect on catalepsy. CONCLUSIONS: These findings suggest that adenosine A2A receptor antagonists may represent an effective treatment for the motor impairments associated with both antipsychotic-induced EPS and PD.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Antipsicóticos/toxicidad , Cafeína/farmacología , Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos/fisiopatología , Haloperidol/toxicidad , Purinas/farmacología , Pirimidinas/antagonistas & inhibidores , Triazoles/antagonistas & inhibidores , Animales , Catalepsia/inducido químicamente , Catalepsia/fisiopatología , Cebus , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiopatología , Relación Dosis-Respuesta a Droga , Globo Pálido/efectos de los fármacos , Globo Pálido/fisiopatología , Examen Neurológico/efectos de los fármacos , Receptor de Adenosina A2A/fisiología , Saimiri , Xantinas/farmacología , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Strategic replacement of the nitrogen of the lead compound 1 in the original cyclic urea series with a carbon resulted in the discovery of a novel, potent and orally more efficacious gamma-lactam series of selective NK(1) antagonists. Optimization of the lactam series culminated in the identification of compounds with high binding affinity and excellent oral CNS activity.
Asunto(s)
Lactamas/química , Antagonistas del Receptor de Neuroquinina-1 , Receptores de Neuroquinina-1/química , Administración Oral , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Modelos Químicos , Estructura Molecular , Nitrógeno/química , Unión Proteica , Relación Estructura-Actividad , Sustancia P/química , Urea/química , VómitosRESUMEN
SCH 58261 is a reported adenosine A(2A) receptor antagonist which is active in rat in vivo models of Parkinson's Disease upon ip administration. However, it has poor selectivity versus the A(1) receptor and does not demonstrate oral activity. Quinoline analogs have improved upon the selectivity and pharmacokinetics of SCH 58261, but were difficult to handle due to poor aqueous solubility. We report the design and synthesis of fused heterocyclic analogs of SCH 58261 with aqueous solubility as well as improved A(2A) receptor binding selectivity and pharmacokinetic properties. In particular, the tetrahydronaphthyridine 4s has excellent A(2A) receptor in vitro binding affinity and selectivity, is active orally in a rat in vivo model of Parkinson's Disease, and has aqueous solubility of 100 microM at physiological pH.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Química Farmacéutica/métodos , Enfermedad de Parkinson/tratamiento farmacológico , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Triazoles/síntesis química , Triazoles/farmacocinética , Adenosina/química , Administración Oral , Animales , Área Bajo la Curva , Modelos Animales de Enfermedad , Diseño de Fármacos , Concentración de Iones de Hidrógeno , Modelos Químicos , Pirimidinas/química , Ratas , Solubilidad , Triazoles/química , Agua/químicaRESUMEN
Neo-natal rats emit ultrasonic vocalizations (USVs) when isolated from their mothers and littermates. Clinically effective anxiolytics reliably reduce USVs, making this behavior a useful animal model of the anxiolytic potential of novel pharmacological approaches to the treatment of anxiety. Here, we assess the hypothesis that USV duration (total time spent vocalizing) is a more sensitive measure of anxiolytic and antidepressant efficacy than USV number by testing established and putative anxiolytics in this model. Negative geotaxis and righting reflex latency were measured to assess sedating properties. The benzodiazepines, CDP (1-10 mg/kg) and diazepam (0.3-3 mg/kg), the 5HT(1A) partial agonist, buspirone (0.3-3 mg/kg), and the mGluR5 antagonist, MTEP (1-30 mg/kg), reduced USV duration at lower doses and to a greater magnitude than USV number. The benzodiazepines, unlike buspirone and MTEP, produced measurable sedation, but it was dissociable from reductions in USV duration. The SSRI antidepressants, fluoxetine (1-30 mg/kg) and citalopram (0.3-30 mg/kg), reduced USV duration more than number with no measurable effect on sedation. The tricyclic antidepressants, imipramine (1-10 mg/kg) and amitriptyline (1-30 mg/kg), had no effect dissociable from sedation. These data support USV duration as a more sensitive and useful measure than USV number in the isolated rat pup model.
Asunto(s)
Ansiolíticos/farmacología , Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Aislamiento Social/psicología , Vocalización Animal/efectos de los fármacos , Animales , Animales Recién Nacidos , Frío , Relación Dosis-Respuesta a Droga , Femenino , Equilibrio Postural/efectos de los fármacos , Embarazo , Ratas , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Receptores de Glutamato Metabotrópico/metabolismo , Reflejo/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , UltrasonidoRESUMEN
Caffeine produces effects on cognitive function particularly relating to aspects of attention such as reaction time. Considering the plasma exposure levels following regular caffeine intake, and the affinity of caffeine for known protein targets, these effects are likely mediated by either the adenosine A(1) or A(2A) receptor. In the present studies, two rat strains [Long-Evans (LE) and CD] were trained to asymptote performance in a test of selective attention, the 5-choice serial reaction time task (5-CSRTT). Next, the effects of caffeine were compared to the selective A(2A) antagonists, SCH 412348 and KW-6002 (Istradefylline), and the A(1) antagonist, DPCPX. Further studies compared the psychostimulant effects of each drug. Finally, we tested the A(2A) agonist, CGS-21680, on 5-CSRTT performance and given the antipsychotic potential of this drug class, studied the interaction between CGS-21680 and amphetamine in this task. Caffeine (3-10mg/kg IP) increased reaction time in both LE and CD rats, with no effect on accuracy, an effect replicated by SCH 412348 (0.1-1mg/kg PO) and KW-6002 (1-3mg/kg PO), but not DPCPX (3-30 mg/kg PO). At least with SCH 412348, these effects were at doses that were not overtly psychostimulant. In contrast, CGS-21680 (0.03-0. 3mg/kg IP) slowed reaction speed and increased omissions. Interestingly, at a comparatively low dose of 0.03 mg/kg, CGS-21680 attenuated the increased premature responding produced by amphetamine (1mg/kg IP). The present results suggest that the attention-enhancing effects of caffeine are mediated through A(2A) receptor blockade, and selective A(2A) receptor antagonists may have potential as therapies for attention-related disorders. Furthermore, the improvement in response control in amphetamine-treated rats following CGS-21680 pretreatment supports the view that A(2A) agonists have potential as novel antipsychotics.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Atención/efectos de los fármacos , Cafeína/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Tiempo de Reacción/efectos de los fármacos , Adenosina/análogos & derivados , Adenosina/farmacología , Anfetamina/farmacología , Animales , Antipsicóticos/farmacología , Conducta de Elección/efectos de los fármacos , Dopamina/fisiología , Relación Dosis-Respuesta a Droga , Masculino , Actividad Motora/efectos de los fármacos , Fenetilaminas/farmacología , Desempeño Psicomotor/efectos de los fármacos , Purinas/farmacología , Ratas , Reflejo de Sobresalto/efectos de los fármacos , Xantinas/farmacologíaRESUMEN
Male 129T2 and C57BL/6J mice were housed either in groups of three (socials) or singly (isolates) at weaning. Six and seven weeks later, prepulse inhibition (PPI), startle reactivity, and locomotor activity (LMA) were measured. Isolation-reared mice of both strains exhibited PPI deficits compared to socially reared controls in at least one of the two PPI test sessions. Isolation rearing had no effect on startle reactivity or habituation and only 129T2 isolates exhibited increased LMA. Isolation rearing induced locomotor hyperactivity and PPI deficits in mice and may be an effective developmental manipulation to use in combination with studies of genetically altered mice.
Asunto(s)
Actividad Motora/fisiología , Inhibición Neural/fisiología , Reflejo de Sobresalto/fisiología , Aislamiento Social , Estimulación Acústica , Análisis de Varianza , Animales , Activación del Canal Iónico/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Modelos Animales , Especificidad de la EspecieRESUMEN
Normalization of altered glutamate neurotransmission through activation of the mGluR2 has emerged as a new approach to treat schizophrenia. These studies describe a potent brain penetrant mGluR2 positive allosteric modulator (PAM), SAR218645. The compound behaves as a selective PAM of mGluR2 in recombinant and native receptor expression systems, increasing the affinity of glutamate at mGluR2 as inferred by competition and GTPγ35S binding assays. SAR218645 augmented the mGluR2-mediated response to glutamate in a rat recombinant mGluR2 forced-coupled Ca2+ mobilization assay. SAR218645 potentiated mGluR2 agonist-induced contralateral turning. When SAR218645 was tested in models of the positive symptoms of schizophrenia, it reduced head twitch behavior induced by DOI, but it failed to inhibit conditioned avoidance and hyperactivity using pharmacological and transgenic models. Results from experiments in models of the cognitive symptoms associated with schizophrenia showed that SAR218645 improved MK-801-induced episodic memory deficits in rats and attenuated working memory impairment in NMDA Nr1neo-/- mice. The drug reversed disrupted latent inhibition and auditory-evoked potential in mice and rats, respectively, two endophenotypes of schizophrenia. This profile positions SAR218645 as a promising candidate for the treatment of cognitive symptoms of patients with schizophrenia, in particular those with abnormal attention and sensory gating abilities.
Asunto(s)
Atención/efectos de los fármacos , Trastornos del Conocimiento/tratamiento farmacológico , Cognición/efectos de los fármacos , Indanos/farmacología , Memoria/efectos de los fármacos , Oxazoles/farmacología , Pirimidinas/farmacología , Receptores AMPA/química , Esquizofrenia/tratamiento farmacológico , Sitio Alostérico , Anfetaminas/farmacología , Animales , Calcio/metabolismo , Corteza Cerebral/metabolismo , AMP Cíclico/metabolismo , Maleato de Dizocilpina/química , Maleato de Dizocilpina/farmacología , Terapia Electroconvulsiva , Células HEK293 , Humanos , Indanos/uso terapéutico , Masculino , Aprendizaje por Laberinto , Memoria a Corto Plazo/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Oxazoles/uso terapéutico , Fenotipo , Pirimidinas/uso terapéutico , Ratas , Ratas Sprague-DawleyRESUMEN
RATIONALE: Modulation of metabotropic glutamate receptor (mGluR) subtypes represents a novel approach for the treatment of neurological and psychiatric disorders. OBJECTIVES: This study was conducted to investigate the role of the mGluR5 and mGluR1 subtypes in the modulation of pain and anxiety. METHODS: The mGluR5 antagonists, 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), and the mGluR1 antagonist, (4-methoxy-phenyl)-(6-methoxy-quinazolin-4-yl)-amine HCl (LY456236), were tested in models of pain [mouse formalin test, rat spinal nerve ligation (SNL)] and anxiety [Vogel conflict, conditioned lick suppression (CLS)], and their efficacious effects were compared to any associated side effects. RESULTS: The systemic administration of MPEP, MTEP, and LY456236 reduced hyperalgesia induced by formalin and mechanical allodynia following SNL. However, only LY456236 completely reversed the allodynia. In the anxiety models, MPEP (3--30 mg/kg), MTEP (3--10 mg/kg), and LY456236 (10--30 mg/kg) produced anxiolytic-like effects similar to the benzodiazepine, chlordiazepoxide (CDP, 6 mg/kg). However, only MPEP and MTEP were able to produce a level of anxiolysis comparable to CDP. In a series of tests examining potential side effects, MPEP and MTEP reduced body temperature and locomotor activity and impaired operant responding for food and rotarod performance at doses of 3--30 and 1--30 mg/kg, respectively. LY456236 reduced operant responding at 30 mg/kg. CONCLUSION: Both mGluR5 and mGluR1 antagonists are effective in models of pain and anxiety. However, an mGluR1 antagonist was more efficacious than the two mGluR5 antagonists in the pain models, which, conversely, appeared more efficacious in the anxiety models. These findings support the potential utility of mGluR5 and mGluR1 antagonists for both the treatment of chronic pain and as novel anxiolytics.
Asunto(s)
Analgésicos/farmacología , Ansiolíticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Piridinas/farmacología , Quinazolinas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Tiazoles/farmacología , Animales , Temperatura Corporal/efectos de los fármacos , Condicionamiento Psicológico/efectos de los fármacos , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Piridinas/toxicidad , Quinazolinas/toxicidad , Ratas , Receptor del Glutamato Metabotropico 5 , Tiazoles/toxicidadRESUMEN
Several neurokinin NK1 receptor antagonists currently being developed for anxiety and depression have reduced affinity for the rat and mouse NK1 receptor compared with human. Consequently, it has proven difficult to test these agents in traditional rat and mouse models of anxiety and depression. This issue has been overcome, in part, by using non-traditional lab species such as the guinea pig and gerbil, which have NK1 receptors closer in homology to human NK1 receptors. However, there are very few reports describing the behavior of gerbils in traditional models of anxiety. The aim of the present study was to determine if the elevated plus-maze, a commonly used anxiety model, could be adapted for the gerbil. Using a specially-designed elevated plus-maze, gerbils exhibited an 'anxious' behavioral profile similar to that observed in rats and mice, i.e., reduced entries into, and time spent exploring, an open, aversive arm. The anxiolytic drugs diazepam (0.03-3 mg/kg i.p.), chlordiazepoxide (0.3-10 mg/kg i.p.), and buspirone (0.3-30 mg/kg s.c.) increased open arm exploration and produced anxiolytic-like effects on risk-assessment behaviors (reduced stretch-attend postures and increased head dips). Of particular interest, the antidepressant drugs imipramine (1-30 mg/kg p.o.), fluoxetine (1-30 mg/kg, p.o.) and paroxetine (0.3-10 mg/kg p.o.) each produced some acute anxiolytic-like activity, without affecting locomotor activity. The antipsychotic, haloperidol, and the psychostimulant, amphetamine, did not produce any anxiolytic-like effects (1-10 mg/kg s.c). The anxiogenic beta-carboline, FG-7142, reduced time spent in the open arm and head dips, and increased stretch-attend postures (1-30 mg/kg, i.p.). These studies have demonstrated that gerbils exhibit an anxiety-like profile on an elevated plus-maze, and that the gerbil elevated plus-maze may have predictive validity for anxiolytics, and antidepressants with potential anxiolytic-like effects.
Asunto(s)
Conducta Animal/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Inhibidores de Captación Adrenérgica/farmacología , Anfetamina/farmacología , Análisis de Varianza , Animales , Ansiolíticos/farmacología , Antidepresivos/farmacología , Antipsicóticos/farmacología , Carbolinas/farmacología , Relación Dosis-Respuesta a Droga , Estudios de Evaluación como Asunto , Conducta Exploratoria/efectos de los fármacos , Femenino , Antagonistas del GABA/farmacología , Gerbillinae , Haloperidol/farmacología , Pruebas Psicológicas/normasRESUMEN
Neurokinin NK1 receptor antagonists may have therapeutic potential in the treatment of anxiety and depression. Species variants in the NK1 receptor result in reduced affinity of NK1 receptor antagonists at rat and mouse NK1 receptors, making it difficult to test NK1 antagonists in traditional preclinical models of anxiety and depression. Gerbil NK1 receptors are similar in homology to the human NK1 receptor. In a companion article, we described the anxiety-like behavioral profile of gerbils on an adapted elevated plus-maze, and the ability of anxiolytic drugs to produce anti-anxiety effects in the gerbil elevated plus-maze. The aim of the present study was to determine whether oral (p.o.) administration of the NK1 receptor antagonists MK-869, L-742,694, L-733,060, CP-99,994, and CP-122,721 produced anxiolytic-like effects in the gerbil elevated plus-maze. Upon testing, all five NK1 antagonists produced anxiolytic-like effects. MK-869 (0.01-3 mg/kg) was the most potent NK1 antagonist, producing anxiolytic-like effects on percentage of open arm time, percentage of open arm entries, stretch-attend postures, and head dips at 0.03-0.3 mg/kg doses. L-742,694 (1-30 mg/kg) and L-733,060 (1-10 mg/kg) produced anxiolytic-like effects on percentage of open arm time and stretch-attend postures at 3-10 mg/kg doses. CP-99,994 (3-30 mg/kg) only produced an anxiolytic-like effect on stretch-attend postures. CP-122,721 (3-30 mg/kg) produced an anxiolytic-like effect on percentage of open arm time at 30 mg/kg. The order of potency of the NK1 antagonists to increase percentage of open arm time was very similar to their potency to block NK1 agonist-induced foot-tapping. These studies demonstrate that neurokinin NK1 receptor antagonists produce anxiolytic-like effects in a novel gerbil elevated plus-maze, and suggest that this is an appropriate model to test NK1 antagonists for preclinical anxiolytic activity.