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
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
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
Overactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been linked to affective disorders such as anxiety and depression. Dampening HPA activity has, therefore, been considered as a possible means of treating affective disorders. Given the important role of vasopressin in modulating the HPA axis, one strategy has focused on inhibiting activity of the vasopressin 1b (V1b) receptor. In animals, V1b receptor antagonists reduce plasma stress hormone levels and have been shown to have an anxiolytic-like effect. Recently, V1B-30N was identified as a highly potent V1b receptor antagonist with selectivity over other vasopressin receptors, which is evaluated here in rodent models of anxiety-like and depression-like behaviors. V1B-30N (1-30mg/kg, IP) dose-dependently reduced separation-induced vocalizations in rat pups without producing any sedative effects in the animals. Similarly, V1B-30N (3-30mg/kg, IP) dose-dependently reduced separation-induced vocalizations in guinea pig pups. In a conflict assay, conditioned lick suppression, V1B-30N (3-30mg/kg, IP) increased punished licking. To assess antidepressive-like properties, V1B-30N (1-30mg/kg) was tested in the mouse and rat forced-swim tests but was found to be inactive. These results are consistent with previous findings with other V1b antagonists, which suggest that acute pharmacological antagonism of the V1b receptor has anxiolytic-like but not antidepressant-like properties.
Asunto(s)
Ansiolíticos/farmacología , Antidepresivos/farmacología , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacología , Ansiedad/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Depresión/tratamiento farmacológico , Receptores de Vasopresinas/metabolismo , Animales , Ansiolíticos/uso terapéutico , Antidepresivos/uso terapéutico , Condicionamiento Psicológico/efectos de los fármacos , Femenino , Cobayas , Masculino , Ratones , Ratas , Natación , Vocalización Animal/efectos de los fármacosRESUMEN
SAR110894 is a novel histamine H3-R ligand, displaying high and selective affinity for human, rat or mouse H3-Rs. SAR110894 is a potent H3-R antagonist at native receptors, reversing R-α-methylhistamine-induced inhibition of electrical field stimulation contraction in the guinea-pig ileum. Additionally, SAR110894 inhibited constitutive GTPγS binding at human H3-Rs demonstrating inverse agonist properties. In behavioral models addressing certain aspects of cognitive impairment associated with schizophrenia (CIAS) and attention deficit/hyperactivity disorder (ADHD), SAR110894 improved memory performances in several variants of the object recognition task in mice (0.3-3 mg/kg, p.o.) or rats (0.3-1 mg/kg, p.o.). Moreover, SAR110894 (1 mg/kg, p.o.) reversed a deficit in working memory in the Y-maze test, following an acute low dose of phencyclidine (PCP) (0.5 mg/kg, i.p.) in mice sensitized by repeated treatment with a high dose of PCP (10 mg/kg, i.p.). In the latent inhibition (LI) model, SAR110894 potentiated LI in saline-treated rats (1 and 3 mg/kg, i.p.) and reversed abnormally persistent LI induced by neonatal nitric oxide synthase (NOS) inhibition in rodents (0.3-3 mg/kg, i.p.). In a social novelty discrimination task in rats, SAR110894 attenuated selective attention deficit induced by neonatal PCP treatment (3 and 10 mg/kg, p.o.) or a parametric modification of the procedure (3 and 10 mg/kg, p.o.). SAR110894 showed efficacy in several animal models related to the cognitive deficits in Alzheimer's disease (AD). It prevented the occurrence of episodic memory deficit induced by scopolamine in rats (0.01-10 mg/kg, p.o.) or by the central infusion of the toxic amyloid fragment ß25â35 in the object recognition test in mice (1 and 3 mg/kg, p.o.). Altogether, these findings suggest that SAR110894 may be of therapeutic interest for the treatment of the cognitive symptoms of AD, schizophrenia and certain aspects of ADHD.
Asunto(s)
Cognición/efectos de los fármacos , Antagonistas de los Receptores Histamínicos H3/farmacología , Animales , Femenino , Antagonistas de los Receptores Histamínicos H3/uso terapéutico , Aprendizaje por Laberinto , Ratones , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Esquizofrenia/tratamiento farmacológicoRESUMEN
NK1 receptor antagonists have been shown to have a variety of physiological and potential therapeutic effects in animal models and in humans. The present studies demonstrate that Rolapitant (SCH 619734, (5S)-8(S)-[[1(R)-[3,5 bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-1,7-diazaspiro[4,5]decan-2-one) is a selective, bioavailable, CNS penetrant neurokinin NK1 receptor antagonist that shows behavioral effects in animals models of emesis. In vitro studies indicate that rolapitant has a high affinity for the human NK1 receptor of 0.66 nM and high selectivity over the human NK2 and NK3 subtypes of >1000-fold, as well as preferential affinity for human, guinea pig, gerbil and monkey NK1 receptors over rat, mouse and rabbit. Rolapitant is a functionally competitive antagonist, as measured by calcium efflux, with a calculated Kb of 0.17 nM. Rolapitant reversed NK1 agonist-induced foot tapping in gerbils following both intravenous and oral administration up to 24 hours at a minimal effective dose (MED) of 0.1 mg/kg. Rolapitant was active at 0.1 and 1 mg/kg in both acute and delayed emesis models in ferrets, respectively, consistent with clinical data for other NK1 antagonists. Clinical efficacy of anti-emetics is highly correlated with efficacy in the ferret emesis model, suggesting rolapitant is a viable clinical candidate for this indication.
Asunto(s)
Antieméticos/administración & dosificación , Antieméticos/metabolismo , Antagonistas del Receptor de Neuroquinina-1 , Receptores de Neuroquinina-1/metabolismo , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/metabolismo , Administración Oral , Animales , Antieméticos/química , Células CHO , Células COS , Chlorocebus aethiops , Cricetinae , Perros , Femenino , Hurones , Gerbillinae , Cobayas , Humanos , Macaca fascicularis , Ratones , Unión Proteica/fisiología , Conejos , Ratas , Compuestos de Espiro/químicaRESUMEN
The endogenous opioid-like peptide, nociceptin, produces anxiolytic-like effects that are mediated via the nociceptin (NOP) receptor. Similarly, synthetic, non-peptide NOP agonists produce robust anxiolytic-like effects although these effects are limited by marked side effects. In the present studies, the effects of a novel NOP receptor agonist, SCH 655842, were examined in rodent models sensitive to anxiolytic drugs and tests measuring potential adverse affects. Oral administration of SCH 655842 produced robust, anxiolytic-like effects in three species, i.e., rat, guinea pig, and mouse. Specifically, SCH 655842 was effective in rat conditioned lick suppression (3-10 mg/kg) and fear-potentiated startle (3-10 mg/kg) tests, a guinea pig pup vocalization test (1-3 mg/kg), as well as in mouse Geller-Seifter (30 mg/kg) and marble burying (30 mg/kg) tests. The anxiolytic-like effect of SCH 655842 in the conditioned lick suppression test was attenuated by the NOP antagonist, J-113397. In mice, SCH 655842 reduced locomotor activity and body temperature at doses similar to the anxiolytic-like dose and these effects were absent in NOP receptor knockout mice. In rats, SCH 655842 did not produce adverse behavioral effects up to doses of 70-100 mg/kg. Pharmacokinetic studies in the rat confirmed dose-related increases in plasma and brain levels of SCH 655842 across a wide oral dose range. Taken together, SCH 655842 may represent a NOP receptor agonist with improved tolerability compared to other members of this class although further studies are necessary to establish whether this extends to higher species.
Asunto(s)
Ansiolíticos/efectos adversos , Ansiolíticos/farmacología , Compuestos de Azabiciclo/efectos adversos , Compuestos de Azabiciclo/farmacología , Receptores Opioides/agonistas , Animales , Ansiolíticos/sangre , Ansiolíticos/farmacocinética , Compuestos de Azabiciclo/sangre , Compuestos de Azabiciclo/farmacocinética , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Temperatura Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Relación Dosis-Respuesta a Droga , Miedo/efectos de los fármacos , Miedo/fisiología , Femenino , Técnicas de Inactivación de Genes , Cobayas , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Ratas , Receptores Opioides/deficiencia , Receptores Opioides/genética , Prueba de Desempeño de Rotación con Aceleración Constante , Especificidad de la Especie , Vocalización Animal/efectos de los fármacos , Receptor de NociceptinaRESUMEN
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
RATIONALE: The psychotomimetic effects of cannabis are believed to be mediated via cannabinoid CB1 receptors. Furthermore, studies have implicated CB1 receptors in the pathophysiology of schizophrenia. OBJECTIVE: These studies investigated the effects of the CB1 receptor antagonist, AVE1625, in acute pharmacological and neurodevelopmental models of schizophrenia. AVE1625 was administered to rodents alone or as a co-treatment with clinically used antipsychotic drugs (APDs). METHODS: The antipsychotic potential of AVE1625 was tested using psychotomimetic-induced hyperactivity and latent inhibition (LI) deficit models. The procognitive profile was assessed using hole board, novel object recognition, auditory evoked potential, and LI techniques. In addition, the side-effect profile was established by measuring catalepsy, antipsychotic-induced weight gain, plasma levels of prolactin, and anxiogenic potential. RESULTS: AVE1625 (1, 3, and 10 mg/kg ip), reversed abnormally persistent LI induced by MK-801 or neonatal nitric oxide synthase inhibition in rodents, and improved both working and episodic memory. AVE1625 was not active in positive symptom models but importantly, it did not diminish the efficacy of APDs. It also decreased catalepsy and weight gain induced by APDs, suggesting that it may decrease APD-induced extrapyramidal side effects (EPS) and compliance. Unlike other CB1 antagonists, AVE1625 did not produce anxiogenic-like effects. CONCLUSIONS: These preclinical data suggest that AVE1625 may be useful to treat the cognitive deficits in schizophrenia and as a co-treatment with currently available antipsychotics. In addition, an improved side-effect profile was seen, with potential to ameliorate the EPS and weight gain issues with currently available treatments.
Asunto(s)
Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Cognición/efectos de los fármacos , Hidrocarburos Halogenados/uso terapéutico , Receptor Cannabinoide CB1/antagonistas & inhibidores , Esquizofrenia/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Estimulación Acústica , Anfetamina/farmacología , Animales , Antipsicóticos/administración & dosificación , Ansiedad/inducido químicamente , Ansiedad/prevención & control , Conducta Animal/efectos de los fármacos , Catalepsia/inducido químicamente , Catalepsia/prevención & control , Condicionamiento Clásico/efectos de los fármacos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Quimioterapia Combinada , Potenciales Evocados Auditivos/efectos de los fármacos , Hidrocarburos Halogenados/administración & dosificación , Hidrocarburos Halogenados/efectos adversos , Masculino , Ratones , Ratones Endogámicos , Ratas , Ratas Sprague-Dawley , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatología , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Aumento de Peso/efectos de los fármacosRESUMEN
The current work extends our previous findings in stress-related disorders, but also addresses the impact of a neurokinin-2 (NK2) antagonist on cognition. Besides efficacy in mood disorders, an NK2 antagonist may have the potential to lack the disinhibitory components and adverse side effects associated with existing clinical treatments. Saredutant (3-30 mg/kg, per os, p.o.) was tested for anxiolytic-like potential in three mouse models: holeboard, stress-induced hyperthermia (SIH) and four-plate. In the holeboard model saredutant (30 mg/kg) showed a trend to increase head dipping without affecting general activity. In the SIH model, saredutant demonstrated a significant reduction in stress-induced temperature at 30 mg/kg, while the number of punished crossings in the four-plate was increased at all doses tested (3-30 mg/kg). While chlordiazepoxide (CDP) demonstrated anxiolytic-like effects in these models, the adverse side effects of benzodiazepines, such as sedation, disinhibition and cognitive deficits are well-documented. Saredutant produced no detrimental effect in three models of cognition: Morris Water Maze (MWM) in rats, spontaneous alternation in a Y-maze in mice and novel objection recognition in mice. In contrast, the benzodiazepine, diazepam (DZM), produced cognitive impairments. NK2 receptor antagonists like saredutant may therefore yield beneficial effects for mood disorders without the adverse effects of current treatments.
Asunto(s)
Antidepresivos/farmacología , Benzamidas/farmacología , Cognición/efectos de los fármacos , Piperidinas/farmacología , Receptores de Neuroquinina-2/antagonistas & inhibidores , Estrés Fisiológico/efectos de los fármacos , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas WistarRESUMEN
Metabotropic glutamate receptor 1 (mGluR1) antagonists interfere with learning and memory; however, their role in motor function is not well elucidated despite their abundance in brain areas implicated in the control of movement. Here, the effects of mGluR1 antagonism on movement, coordination, and motor learning were investigated. JNJ16259685, a selective mGluR1 antagonist (negative allosteric modulator), was tested in assays of motor skill, and motor learning in rats and mice. JNJ16259685 produced very minimal effects on locomotor activity and posture up to a dose of 30 mg/kg. Motor skill was unaffected for well-learned tasks (up to 30 mg/kg) in rats, but impaired in mice. Both rats and mice rats were profoundly impaired (0.3 mg/kg) in the acquisition of a novel motor skill (rotarod). These results implicate the mGluR1 receptor in the acquisition of novel motor skills. JNJ16259685 dramatically reduced rearing behavior, exploration of a novel environment and lever pressing for a food reward (rat: 0.3 mg/kg; mouse: 1 mg/kg). JNJ16259685 (30 mg/kg) had no effect on reflexive startle responses to loud auditory stimuli or foot shock in mice. Previous groups have proposed that mGluR1 antagonists induce a general reduction in motivation. The effects seen here to reduce exploration and reward are consistent with that hypothesis. Pharmacological inhibition of the mGluR1 receptor has a modest effect on motor function but blocks motor learning and may reduce motivation to perform simple behaviors.
Asunto(s)
Actividad Motora/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , Quinolinas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Antagonistas de Aminoácidos Excitadores/farmacología , Aprendizaje/efectos de los fármacos , Aprendizaje/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Actividad Motora/fisiología , Desempeño Psicomotor/fisiología , Ratas , Ratas Long-Evans , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiologíaRESUMEN
Parkinson's Disease (PD) and Extrapyramidal Syndrome (EPS) are movement disorders that result from degeneration of the dopaminergic input to the striatum and chronic inhibition of striatal dopamine D(2) receptors by antipsychotics, respectively. Adenosine A(2A) receptors are selectively localized in the basal ganglia, primarily in the striatopallidal ("indirect") pathway, where they appear to operate in concert with D(2) receptors and have been suggested to drive striatopallidal output balance. In cases of dopaminergic hypofunction, A(2A) receptor activation contributes to the overdrive of the indirect pathway. A(2A) receptor antagonists, therefore, have the potential to restore this inhibitor imbalance. Consequently, A(2A) receptor antagonists have therapeutic potential in diseases of dopaminergic hypofunction such as PD and EPS. Targeting the A(2A) receptor may also be a way to avoid the issues associated with direct dopamine agonists. Recently, preladenant was identified as a potent and highly selective A(2A) receptor antagonist, and has produced a significant improvement in motor function in rodent models of PD. Here we investigate the effects of preladenant in two primate movement disorder models. In MPTP-treated cynomolgus monkeys, preladenant (1 or 3 mg/kg; PO) improved motor ability and did not evoke any dopaminergic-mediated dyskinetic or motor complications. In Cebus apella monkeys with a history of chronic haloperidol treatment, preladenant (0.3-3.0 mg/kg; PO) delayed the onset of EPS symptoms evoked by an acute haloperidol challenge. Collectively, these data support the use of preladenant for the treatment of PD and antipsychotic-induced movement disorders.
Asunto(s)
Enfermedades de los Ganglios Basales/tratamiento farmacológico , Ganglios Basales/metabolismo , Actividad Motora/efectos de los fármacos , Pirimidinas/uso terapéutico , Receptor de Adenosina A2A/metabolismo , Triazoles/uso terapéutico , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Antagonistas del Receptor de Adenosina A2 , Análisis de Varianza , Animales , Área Bajo la Curva , Enfermedades de los Ganglios Basales/inducido químicamente , Enfermedades de los Ganglios Basales/metabolismo , Cebus , Modelos Animales de Enfermedad , Femenino , Macaca fascicularis , MasculinoRESUMEN
We describe the pharmacological and pharmacokinetic profiles of SCH 486757, a nociceptin/orphanin FQ peptide (NOP) receptor agonist that has recently entered human clinical trials for cough. SCH 486757 selectively binds human NOP receptor (K(i)=4.6+/-0.61nM) over classical opioid receptors. In a guinea pig capsaicin cough model, SCH 486757 (0.01-1mg/kg) suppressed cough at 2, 4, and 6h post oral administration with a maximum efficacy occurring at 4h equivalent to codeine, hydrocodone, dextromethorphan and baclofen. The antitussive effects of SCH 486757 (3.0mg/kg, p.o.) was blocked by the NOP receptor antagonist J113397 (12mg/kg, i.p.) but not by naltrexone (10mg/kg, p.o.). SCH 486757 does not produce tolerance to its antitussive activity after a 5-day BID dosing regimen. After acute and chronic dosing paradigms, SCH 486757 (1mg/kg) inhibited capsaicin-evoked coughing by 46+/-9% and 40+/-11%, respectively. In a feline mechanically-evoked cough model, SCH 486757 produces a maximum inhibition of cough and expiratory abdominal electromyogram amplitude of 59 and 61%, respectively. SCH 486757 did not significantly affect inspiratory electromyogram amplitude. We examined the abuse potential of SCH 486757 (10mg/kg, p.o.) in a rat conditioned place preference procedure which is sensitive to classical drugs of abuse, such as amphetamine and morphine. SCH 486757 was without effect in this model. Finally, SCH 486757 displays a good oral pharmacokinetic profile in the guinea pig, rat and dog. We conclude that SCH 486757 has a favorable antitussive profile in preclinical animal models.
Asunto(s)
Antitusígenos/uso terapéutico , Tos/tratamiento farmacológico , Receptores Opioides/agonistas , Animales , Compuestos de Azabiciclo/farmacología , Gatos , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Cobayas , Masculino , Pirimidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Opioides/metabolismo , 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
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
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
RATIONALE: SSR103800 and SSR504734 are novel glycine transport 1 (GlyT1) inhibitors with therapeutic potential for the treatment of schizophrenia. OBJECTIVE: The present studies investigated the effects of GlyT1 inhibitors in acute pharmacological and neurodevelopmental models of schizophrenia using latent inhibition in the rat; these latent inhibition (LI) models are believed to be predictive for treatments of positive, negative, and cognitive aspects of schizophrenia. MATERIALS AND METHODS: LI, the poorer conditioning to a previously irrelevant stimulus, was measured in a conditioned emotional response procedure in male rats. The effects of SSR103800 or SSR504734 (both at 1, 3, and 10 mg/kg, i.p.) were determined on amphetamine-induced disrupted LI, MK-801-induced abnormally persistent LI, and neurodevelopmentally induced abnormally persistent LI in adult animals that had been neonatally treated with a nitric oxide synthase inhibitor. RESULTS: SSR103800 (1 and 3 mg/kg) and SSR504734 (1 and 10 mg/kg) potentiated LI under conditions where LI was not present in nontreated controls and SSR103800 (1 mg/kg) reversed amphetamine-induced disrupted LI while not affecting LI on its own. Additionally, SSR103800 (1 and 3 mg/kg) and SSR504734 (3 and 10 mg/kg) reversed abnormally persistent LI induced by MK-801. In the neurodevelopmental model, SSR504734 (3 and 10 mg/kg) reverted the LI back to control (normal) levels. CONCLUSIONS: These preclinical data, from acute and neurodevelopmental models, suggest that GlyT1 inhibition may exhibit activity in the positive, negative, and cognitive symptom domains of schizophrenia.
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Envejecimiento/psicología , Antipsicóticos/farmacología , Cognición/efectos de los fármacos , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Reflejo de Sobresalto/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Psicología del Esquizofrénico , Anfetamina/antagonistas & inhibidores , Anfetamina/toxicidad , Animales , Animales Recién Nacidos , Benzamidas/farmacología , Estimulantes del Sistema Nervioso Central/toxicidad , Condicionamiento Operante/efectos de los fármacos , Maleato de Dizocilpina/antagonistas & inhibidores , Maleato de Dizocilpina/toxicidad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Antagonistas de Aminoácidos Excitadores/toxicidad , Haloperidol/farmacología , Masculino , Nitroarginina/farmacología , Piperidinas/farmacología , Ratas , Ratas WistarRESUMEN
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.
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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.
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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.