RESUMEN
The novel mGlu2/3 receptor antagonist, LY3020371, has been shown to produce antidepressant-like effects comparable to that of the clinically-effective antidepressant ketamine. In the present study, we investigated whether LY3020371 would be predicted to be free of the side-effects and safety pharmacology issues associated with ketamine. In contrast to ketamine, LY3020371 produced small increases in locomotion and did not impair motor performance on an inverted screen. Ketamine, but not LY3020371, increased dopamine efflux in the nucleus accumbens of rats. Ketamine also produced cognitively-impairing effects in rats in a T-maze and in a psychomotor vigilance task and altered theta synchrony between the hippocampus and mPFC, whereas LY3020371 had either no significant impact or lesser effects in these assays. In mice, ketamine, but not LY3020371, negatively affected spontaneous alternation in a Y-maze. Rats were trained to discriminate LY3020371 from vehicle where 30mg/kg produced 100% drug-appropriate responding and the ED50 for LY3020371 was 9.4mg/kg, i.p. In rats discriminating LY3020371, neither d-amphetamine nor phencyclidine fully substituted for LY3020371 (35-45%) and the mGlu2/3 receptor agonist LY354740 partially attenuated the discriminative stimulus effects of LY3020371. These are the first data to demonstrate the discriminative stimulus effects of an mGlu2/3 receptor antagonist. Some alterations were suggested to occur in the density of mGlu2/3 receptor binding sites in the drug discrimination rats relative to their age-matched non-drug-exposed controls. In preclinical toxicology studies of 14day dosing of doses up to 1000mg/kg, i.v. in rats and up to 500m/kg, i.v. in Cynomologous monkeys, LY3020371 produced uM plasma exposures without producing critical toxicological findings. It is concluded that LY3020371 does not recapitulate the motor, cognitive, subjective, neurochemical, electrophysiological, or toxicological findings reported with ketamine. Thus, LY3020371 possesses both the efficacy signatures of a rapidly-acting antidepressant and a safety profile enabling proof of concept studies in patients.
Asunto(s)
Cognición/efectos de los fármacos , Ciclohexanos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Ketamina/toxicidad , Actividad Motora/efectos de los fármacos , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Trastornos Relacionados con Sustancias/etiología , Animales , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: Olanzapine (OLZ) is unique among currently available antipsychotic medications in its antagonism of a range of receptor systems including dopamine, norepinephrine, serotonin, acetylcholine, and histamine. Olanzapine's mechanistic complexity provides a broad efficacy profile in patients with schizophrenia and acute, pure or mixed mania. Patients experience symptomatic relief of mania, anxiety, hallucinations, delusions, and agitation/aggression and reduced depressive, negative, and some cognitive symptoms. This paper will review the safety profile of OLZ, focusing on the elderly, where data are available. METHOD: Preclinical and clinical studies of OLZ are reviewed, with emphasis on its possible effects on the cholinergic system and the histamine H(1) receptor. Weight change and related metabolic considerations, cardiac and cardiovascular safety, and motor function during treatment with OLZ are also reviewed. RESULTS AND CONCLUSION: In vitro receptor characterization methods, when done using physiologically relevant conditions allow accurate prediction of the relatively low rate of anticholinergic-like adverse events, extrapyramidal symptoms, and cardiovascular adverse events during treatment with OLZ. Currently available clinical data suggest olanzapine is predictably safe in treating adult patients of any age with schizophrenia and acute bipolar mania, as well as in treatment of patients with some types of neurodegenerative disorders.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Pirenzepina/análogos & derivados , Pirenzepina/efectos adversos , Sistemas de Registro de Reacción Adversa a Medicamentos , Anciano , Animales , Benzodiazepinas , Encéfalo/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Humanos , Examen Neurológico/efectos de los fármacos , Olanzapina , Pirenzepina/uso terapéutico , Receptores de Neurotransmisores/efectos de los fármacosRESUMEN
Recent studies have demonstrated that selective 5-HT(1F) receptor agonists inhibit neurogenic dural inflammation, a model of migraine headache, indicating that these compounds may be effective therapies for the treatment of migraine pain. This communication describes the synthesis and discovery of a novel compound, N-[3-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl]-4-fluorobenzamide (4), which possesses high binding affinity and selectivity at the 5-HT(1F) receptor relative to more than 40 other serotonergic and nonserotonergic receptors examined.
Asunto(s)
Benzamidas/síntesis química , Indoles/síntesis química , Trastornos Migrañosos/tratamiento farmacológico , Receptores de Serotonina/efectos de los fármacos , Agonistas de Receptores de Serotonina/síntesis química , Animales , Benzamidas/química , Benzamidas/metabolismo , Benzamidas/farmacología , Línea Celular , Duramadre/efectos de los fármacos , Cobayas , Humanos , Técnicas In Vitro , Indoles/química , Indoles/metabolismo , Indoles/farmacología , Inflamación , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Conejos , Ratas , Receptores de Neurotransmisores/metabolismo , Receptores de Serotonina/metabolismo , Vena Safena/efectos de los fármacos , Vena Safena/fisiología , Agonistas de Receptores de Serotonina/química , Agonistas de Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/farmacología , Relación Estructura-Actividad , Receptor de Serotonina 5-HT1FRESUMEN
The ability of the partial muscarinic agonist pilocarpine to increase in vivo phosphoinositide (PI) hydrolysis in mouse brain was compared to two full agonists. Pilocarpine increased in vivo phosphoinositide (PI) hydrolysis in cortex, striatum, and to the greatest extent in the hippocampus. Pilocarpine injected either subcutaneously or intracerebroventricularly robustly increased in vivo PI hydrolysis in hippocampus up to 500% of control levels and the increases were blocked by the muscarinic antagonist scopolamine. The increases in vivo PI hydrolysis induced by pilocarpine were 60-75% of the magnitude of the full muscarinic agonists oxotremorine-M and cis-dioxolane. The muscarinic M(1) preferring antagonist pirenzepine potently blocked pilocarpine-induced increases in in vivo PI hydrolysis, consistent with the increase being mediated by M(1) receptors. Since pilocarpine is a relatively weak partial agonist, these data suggest a substantial level of receptor reserve for the PI response in mouse hippocampus.
Asunto(s)
Acetilcolina/metabolismo , Fibras Colinérgicas/metabolismo , Hipocampo/metabolismo , Agonistas Muscarínicos/metabolismo , Fosfatidilinositoles/metabolismo , Receptores Muscarínicos/metabolismo , Transmisión Sináptica/fisiología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Animales , Fibras Colinérgicas/efectos de los fármacos , Dioxolanos/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas/fisiología , Hipocampo/efectos de los fármacos , Hidrólisis/efectos de los fármacos , Litio/farmacología , Masculino , Ratones , Antagonistas Muscarínicos/farmacología , Oxotremorina/farmacología , Pilocarpina/metabolismo , Pirenzepina/farmacología , Receptores Muscarínicos/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacosRESUMEN
(5R,6R)-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane) (BuTAC) is a novel, selective muscarinic receptor ligand with partial agonist mode of action at muscarinic M2 and M4 and antagonist mode of action at M1, M3 and M5 receptor subtypes in cloned cell lines. BuTAC exhibits functional dopamine receptor antagonism despite its lack of affinity for dopamine receptors, and parasympathomimetic effects in mice are produced only at doses well beyond the doses exhibiting the antipsychotic-like effects. In the present study we investigated the effects of BuTAC and the antipsychotic compounds clozapine, sertindole and olanzapine using one trial passive avoidance with mice as a model of learning and memory. Pharmacologically relevant doses of BuTAC and reference antipsychotics were identified, based on inhibition of apomorphine-induced climbing in mice as an assay measuring antidopaminergic potency. When ratios between the minimum effective dose (MED) for impairment of retention in passive avoidance and the MED for inhibition of apomorphine-induced climbing were calculated, BuTAC displayed a high ratio of >10, compared with clozapine (0.3), sertindole (3) and olanzapine (3). These data suggest that BuTAC is a potential novel antipsychotic which may have favourable effects on aspects of learning and memory.
Asunto(s)
Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Reacción de Prevención/efectos de los fármacos , Modelos Animales de Enfermedad , Memoria/efectos de los fármacos , Receptores Muscarínicos/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Animales , Conducta Animal/efectos de los fármacos , Masculino , RatonesRESUMEN
(5R,6R)-6-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[ 3.2.1]octane (PTAC) is a selective muscarinic receptor ligand. The compound exhibits high affinity for central muscarinic receptors with partial agonist mode of action at muscarinic M(2) and M(4) and antagonist mode of action at muscarinic M(1), M(3) and M(5) receptor subtypes. The compound was earlier reported to exhibit functional dopamine receptor antagonism in rodents despite its lack of affinity for dopamine receptors. In the present study, we report that PTAC, as well as the muscarinic receptor agonists pilocarpine and oxotremorine, dose-dependently decreased rates of intravenous self-administration (fixed ratio 1) of the indirect dopamine receptor agonist cocaine in drug naive mice. Similar decreases in cocaine self-administration rates were obtained with the dopamine receptor antagonists olanzapine, clozapine, risperidone, fluphenazine and haloperidol. These findings suggest that compounds with partial muscarinic receptor agonist mode of action may be used in the medical treatment of cocaine abuse.
Asunto(s)
Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Agonistas Muscarínicos/farmacología , Animales , Antipsicóticos/farmacología , Compuestos Bicíclicos con Puentes/farmacología , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Oxotremorina/farmacología , Pilocarpina/farmacología , Autoadministración , Tiadiazoles/farmacologíaRESUMEN
LY426965 [(2S)-(+)-1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]2-methyl- 2-phenyl-1-butanone monohydrochloride] is a novel compound with high affinity for the cloned human 5-hydroxytryptamine (HT)(1A) receptor (K(i) = 4.66 nM) and 20-fold or greater selectivity over other serotonin and nonserotonin receptor subtypes. Both in vitro and in vivo studies indicate that LY426965 is a full antagonist and has no partial agonist properties. LY426965 did not stimulate [(35)S]guanosine-5'-O-(3-thio) triphosphate (GTPgammaS) binding to homogenates of cells expressing the cloned human 5-HT(1A) receptor in vitro but did inhibit 300 nM 5-HT-stimulated [(35)S]GTPgammaS binding with a K(i) value of 3.07 nM. After both p.o. and s.c. administration, LY426965 blocked the lower lip retraction, flat body posture, hypothermia, and increase in rat serum corticosterone induced by the 5-HT(1A) agonist 8-OH-DPAT (8-hydroxy-2-dipropylaminotetralin). In pigeons, LY426965 dose-dependently blocked the stimulus cue induced by 8-OH-DPAT but had no 8-OH-DPAT-like discriminative properties. LY426965 completely reversed the effects of nicotine withdrawal on the auditory startle reflex in rats. In microdialysis experiments, LY426965 administered together with fluoxetine significantly increased extracellular levels of serotonin above those achievable with fluoxetine alone. In electrophysiological studies, the administration of LY426965 produced a slight elevation of the firing rate of 5-HT neurons in the dorsal raphe nucleus of anesthetized rats and both blocked and reversed the effects of fluoxetine on 5-HT neuronal activity. These preclinical results indicate that LY426965 is a selective, full 5-HT(1A) antagonist that may have clinical use as pharmacotherapy for smoking cessation and depression and related disorders.
Asunto(s)
Fluoxetina/farmacología , Nicotina/efectos adversos , Piperidinas/farmacología , Receptores de Serotonina/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Antagonistas de la Serotonina/farmacología , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , 8-Hidroxi-2-(di-n-propilamino)tetralin/antagonistas & inhibidores , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Estimulación Acústica , Animales , Temperatura Corporal/efectos de los fármacos , Columbidae , Corticosterona/sangre , Depresión/tratamiento farmacológico , Aprendizaje Discriminativo/efectos de los fármacos , Interacciones Farmacológicas , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Labio/efectos de los fármacos , Masculino , Microdiálisis , Neuronas/efectos de los fármacos , Neuronas/fisiología , Postura , Ratas , Ratas Long-Evans , Ratas Sprague-Dawley , Receptores de Serotonina/metabolismo , Receptores de Serotonina 5-HT1 , Reflejo de Sobresalto/efectos de los fármacos , Serotonina/farmacología , Antagonistas de la Serotonina/metabolismo , Agonistas de Receptores de Serotonina/farmacología , Cese del Hábito de Fumar , Síndrome de Abstinencia a Sustancias/etiología , Radioisótopos de AzufreRESUMEN
Muscarinic agonists stimulated arachidonic acid release from 10- to 32-fold in Chinese hamster ovary (CHO) cells transfected with muscarinic M1, M3 and M5 receptor subtypes. Muscarinic agonists liberated arachidonic acid from the cAMP-coupled M2 and M4 cells only in the presence of ATP. Partial agonists were less efficacious at liberating arachidonic acid than full agonists. The ability of muscarinic agonists to liberate arachidonic acid and stimulate phosphoinositide hydrolysis in the same CHO M1, M3 and M5 cells was well correlated; however, partial agonists were more efficacious at stimulating phosphoinositide hydrolysis than arachidonic acid release. The efficacy and potency of 13 muscarinic agonists to liberate arachidonic acid was characterised. Influx of external calcium was required for arachidonic acid release even after initiation of agonist-induced release. It is concluded that arachidonic acid release is a simple assay suitable for evaluation of muscarinic agonists, antagonists and the flux of external calcium into cells.
Asunto(s)
Ácido Araquidónico/metabolismo , Agonistas Muscarínicos/metabolismo , Oxotremorina/análogos & derivados , Receptores Muscarínicos/metabolismo , Animales , Células CHO , Calcio/fisiología , Quelantes/farmacología , Cricetinae , Ácido Egtácico/farmacología , Humanos , Hidrólisis , Agonistas Muscarínicos/farmacología , Antagonistas Muscarínicos/farmacología , Oxotremorina/metabolismo , Oxotremorina/farmacología , Pirenzepina/farmacología , Receptores Muscarínicos/genética , Factores de Tiempo , TransfecciónRESUMEN
The purpose of our studies was to determine the effects of muscarinic receptor agonists on conditioned avoidance responding in the rat. Rats were trained to avoid or escape an electric shock delivered to the feet in a discrete trial procedure. The muscarinic receptor agonists pilocarpine and [2-ethyl-8-methyl-2,8-diazaspiro(4. 5)decane-1,3-dione] hydrochloride (RS86) and the cholinesterase inhibitor physostigmine all decreased the percentage of avoidance responses at doses that produced less than approximately 30% response failures. Similar results were obtained with the antipsychotic drugs haloperidol, trifluoperazine, chlorpromazine, and clozapine. However, the benzodiazepine anxiolytic diazepam did not decrease avoidance responding up to doses that produced ataxia. On the other hand, oxotremorine and arecoline decreased avoidance responding only by producing response failures, whereas aceclidine produced intermediate changes. The muscarinic receptor antagonists scopolamine, trihexyphenidyl, and benztropine were without effect when administered alone but antagonized the decreases in avoidance responding produced by pilocarpine and RS86. Scopolamine had little effect on the decreases in avoidance responding produced by haloperidol. The newer muscarinic receptor partial agonists or agonist/antagonists [R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2. 2]octane-3-acetonitrile] hydrochloride, talsaclidine, milameline, and xanomeline also produced dose-related decreases in avoidance responding. Our results demonstrate that muscarinic receptor agonists can decrease avoidance responding in a manner similar to dopamine-receptor antipsychotic drugs, suggesting that muscarinic receptor agonists may provide an alternative approach to the treatment of psychosis.
Asunto(s)
Antipsicóticos/farmacología , Reacción de Prevención/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Agonistas Muscarínicos/farmacología , Animales , Inhibidores de la Colinesterasa/farmacología , Depresión Química , Diazepam/farmacología , Relación Dosis-Respuesta a Droga , Haloperidol/farmacología , Masculino , Pilocarpina/farmacología , Ratas , Ratas Endogámicas F344 , Receptores Muscarínicos/efectos de los fármacos , Escopolamina/farmacología , Succinimidas/farmacologíaRESUMEN
Two new series of 1-(1,2,5-thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2, 6)]heptanes were synthesized and evaluated for their in vitro activity in cell lines transfected with either the human M1 or M2 receptor. 3-Phenyl-2-propyn-1-yloxy and -1-ylthio analogues substituted with halogen in the meta position showed high functional potency, efficacy, and selectivity toward the M1 receptor subtype. A quite unique functional M1 receptor selectivity was observed for compounds 8b, 8d, 8f, 9b, 9d, and 9f. Bioavailability studies in rats indicated an oral bioavailability of about 20-30%, with the N-oxide as the only detected metabolite.
Asunto(s)
Compuestos Aza/química , Heptanos/química , Agonistas Muscarínicos/química , Receptores Muscarínicos/efectos de los fármacos , Tiadiazoles/química , Animales , Compuestos Aza/síntesis química , Compuestos Aza/farmacocinética , Compuestos Aza/farmacología , Unión Competitiva , Disponibilidad Biológica , Células CHO , Línea Celular , Corteza Cerebral/metabolismo , Cricetinae , AMP Cíclico/biosíntesis , Heptanos/síntesis química , Heptanos/farmacocinética , Heptanos/farmacología , Humanos , Hidrólisis , Técnicas In Vitro , Ratones , Agonistas Muscarínicos/síntesis química , Agonistas Muscarínicos/farmacocinética , Agonistas Muscarínicos/farmacología , Fosfatidilinositoles/metabolismo , Ensayo de Unión Radioligante , Ratas , Receptor Muscarínico M1 , Receptor Muscarínico M2 , Receptores Muscarínicos/metabolismo , Relación Estructura-Actividad , Tiadiazoles/síntesis química , Tiadiazoles/farmacocinética , Tiadiazoles/farmacología , TransfecciónRESUMEN
The purpose of the present studies was to directly compare the pharmacology of the muscarinic cholinergic receptors coupled to carbachol-induced relaxation and contraction of the intact and the endothelium-denuded rabbit thoracic aorta, respectively. The order of potencies of agonists for producing relaxation in the intact aorta was similar to that for producing contraction in the denuded aorta. In both preparations, the partial agonists pilocarpine, McN-A-343, and RS86 functioned as antagonists, indicating a lack of receptor reserve in both preparations. Further, the pA2 values for antagonists in both tissues were virtually identical and were consistent with the pharmacology of M3 receptors.
Asunto(s)
Aorta Torácica/efectos de los fármacos , Agonistas Muscarínicos/farmacología , Antagonistas Muscarínicos/farmacología , Receptores Muscarínicos/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Animales , Aorta Torácica/fisiología , Carbacol/farmacología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiología , Masculino , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Conejos , Receptor Muscarínico M3 , Receptores Muscarínicos/fisiologíaRESUMEN
The atypical antipsychotic olanzapine has relatively high affinity for a number of neuronal receptors in radioreceptor binding assays. The ability of olanzapine to activate or antagonize a number of neuronal receptors was investigated in vitro, in cell lines transfected selectively with receptor subtypes and in receptor-selective isolated tissue studies. Olanzapine had no agonist activity at any of the receptors examined. However, olanzapine was a potent antagonist of 5-HT-stimulated increases in IP3 in cell lines transfected with 5-HT2A or 5-HT2B receptors with IC50 values of 30-40 nM. Olanzapine weakly blocked 5-HT-induced formation of IP3 in cell lines transfected with 5-HT2c receptors, but in this cell line potently inhibited 5-HT-stimulated [35S]GTP gamma S binding with a Ki value of 15 nM. Olanzapine blocked dopamine-stimulated adenylyl cyclase in rat retina with modest potency (Ki = 69 nM), consistent with its relatively low affinity for dopamine D1 receptors. Olanzapine blocked agonist-induced activities at the muscarinic receptor subtypes M1, M2, M3, and M5 with Ki values of 70, 622, 126, and 82 nM, respectively. In studies using cell lines transfected with muscarinic M4 receptors, olanzapine and the atypical antipsychotic clozapine did not have agonist activities as determined with cAMP inhibition and stimulation assays, arachidonic acid release and [35S]GTP gamma S binding assays. However, olanzapine antagonized agonist-induced effects in muscarinic M4 cells with a Ki value of 350 nM. In isolated tissue studies, olanzapine potently blocked agonist-induced effects at alpha 1-adrenergic and histamine H1 receptors (KB = 9 and 19 nM, respectively). Thus, olanzapine was an antagonist at all receptors investigated and was a particularly potent antagonist at 5-HT2A, 5-HT2B, 5-HT2C, alpha 1-adrenergic and histamine H1 receptors. Olanzapine was a weaker antagonist at muscarinic and dopamine D1 receptors.
Asunto(s)
Pirenzepina/análogos & derivados , Receptores Adrenérgicos alfa/efectos de los fármacos , Receptores de Dopamina D1/efectos de los fármacos , Receptores Histamínicos H1/efectos de los fármacos , Receptores Muscarínicos/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Adenilil Ciclasas/metabolismo , Animales , Benzodiazepinas , Células Cultivadas , Cricetinae , Cinética , Olanzapina , Pirenzepina/antagonistas & inhibidores , Pirenzepina/metabolismo , Ratas , Retina/metabolismoRESUMEN
Olanzapine, an atypical antipsychotic, has a broad receptor binding profile, which may account for its pharmacological effects in schizophrenia. In vitro receptor binding studies showed a high affinity for dopamine D2, D3, and D4 receptors; all 5-HT2 receptor subtypes and the 5-HT6 receptor; muscarinic receptors, especially the M1 subtype: and alpha 1-adrenergic receptors. In vivo studies showed that olanzapine had potent activity at D2 and 5-HT2A receptors, but much less activity at D1 and muscarinic receptors, and that it inhibited dopaminergic neurons in the A10 but not the A9 tract, suggesting that this agent will not cause extrapyramidal side-effects (EPS). Microdialysis studies showed that olanzapine increased the extracellular levels of norepinephrine and dopamine, but not 5-HT, in the prefrontal cortex, and increased extracellular dopamine levels in the neostriatum and nucleus accumbens, areas of the brain associated with schizophrenia. Studies of gene expression showed that olanzapine 10 mg/kg also increased Fos expression in the prefrontal cortex, the dorsolateral striatum, and the nucleus accumbens. These findings are consistent with the effectiveness of olanzapine on both negative and positive symptoms and suggest that, with careful dosing, olanzapine should not cause EPS.
Asunto(s)
Antipsicóticos/metabolismo , Pirenzepina/análogos & derivados , Esquizofrenia/metabolismo , Animales , Antipsicóticos/uso terapéutico , Benzodiazepinas , Expresión Génica/efectos de los fármacos , Humanos , Olanzapina , Pirenzepina/metabolismo , Pirenzepina/uso terapéutico , Receptores Dopaminérgicos/metabolismo , Receptores Muscarínicos/metabolismo , Receptores de Serotonina/metabolismo , Esquizofrenia/tratamiento farmacológicoRESUMEN
The role of muscarinic receptors in schizophrenia was investigated using the muscarinic agonist PTAC. PTAC was highly selective for muscarinic receptors, was a partial agonist at muscarinic M2/M4 receptors and an antagonist at M1, M3 and M5 receptors. PTAC was highly active in animal models predictive of antipsychotic behavior including inhibition of conditioned avoidance responding in rats and blockade of apomorphine-induced climbing behavior in mice. d-Amphetamine-induced Fos expression in rat nucleus accumbens was inhibited by PTAC, thus directly demonstrating the ability of PTAC to modulate DA activity. In electrophysiological studies in rats, PTAC acutely inhibited the firing of A10 DA cells and after chronic administration decreased the number of spontaneously firing DA cells in the A10 brain area. However, PTAC did not appreciably alter the firing of A9 DA cells. Thus, PTAC appears to have novel antipsychotic-like activity and these data suggest that muscarinic compounds such as PTAC may represent a new class of antipsychotic agents.
Asunto(s)
Antipsicóticos/farmacología , Compuestos Bicíclicos con Puentes/farmacología , Receptores Muscarínicos/fisiología , Esquizofrenia/tratamiento farmacológico , Tiadiazoles/farmacología , Animales , Antipsicóticos/administración & dosificación , Antipsicóticos/metabolismo , Antipsicóticos/uso terapéutico , Conducta Animal/efectos de los fármacos , Unión Competitiva , Compuestos Bicíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos con Puentes/metabolismo , Compuestos Bicíclicos con Puentes/uso terapéutico , Células CHO , Catalepsia/inducido químicamente , Cricetinae , Dopamina/metabolismo , Dopaminérgicos/farmacología , Relación Dosis-Respuesta a Droga , Electrofisiología , Agonistas Muscarínicos/farmacología , Antagonistas Muscarínicos/farmacología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Receptores Muscarínicos/metabolismo , Esquizofrenia/fisiopatología , Sistemas de Mensajero Secundario/efectos de los fármacos , Tiadiazoles/administración & dosificación , Tiadiazoles/metabolismo , Tiadiazoles/uso terapéuticoRESUMEN
(5R,6R) 6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]oc tane (PTAC) is a selective muscarinic ligand with high affinity for central muscarinic receptors, agonist mode of action at the muscarinic M2 and M4 receptor subtypes and substantially less or no affinity for central dopamine receptors. In the present study PTAC, as well as the muscarinic agonists oxotremorine, RS86 and pilocarpine, inhibited dopamine D1 and D2 receptor agonist induced contralateral rotation in unilaterally 6-OHDA lesioned rats. The dose of SKF 38393 used to induce contralateral rotation also caused an intense Fos protein immunoreactivity in the rat dorsolateral striatum on the lesioned site which was inhibited by PTAC indicating that the inhibition of rotation by PTAC was not due to non-specific peripheral side effects.
Asunto(s)
Fibras Colinérgicas/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Agonistas Muscarínicos/farmacología , Oxotremorina/farmacología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Anticuerpos , Antipsicóticos/farmacología , Química Encefálica/efectos de los fármacos , Compuestos Bicíclicos con Puentes/farmacología , Fibras Colinérgicas/química , Dopamina/fisiología , Agonistas de Dopamina/farmacología , Masculino , Oxidopamina , Parasimpaticomiméticos/farmacología , Pilocarpina/farmacología , Proteínas Proto-Oncogénicas c-fos/análisis , Proteínas Proto-Oncogénicas c-fos/inmunología , Ratas , Ratas Sprague-Dawley , Sustancia Negra/citología , Sustancia Negra/metabolismo , Succinimidas/farmacología , Simpaticolíticos , Tiadiazoles/farmacologíaRESUMEN
Muscarinic agonists were tested in two models indicative of clinical antipsychotic activity: conditioned avoidance responding (CAR) in rats and inhibition of apomorphine-induced climbing in mice. The standard muscarinic agonists oxotremorine and pilocarpine were both active in these tests but showed little separation between efficacy and cholinergic side effects. Structure-activity relationships of the alkylthio-1,2,5-thiadiazole azacyclic type muscarinic partial agonists are shown, revealing the exo-6-(3-propyl/butylthio-1,2, 5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane analogues (4a,b and 9a, b) to be the most potent antipsychotic agents with large separation between efficacy and cholinergic side effects. The lack of enantiomeric selectivity suggests the pharmacophoric elements are in the mirror plane of the compounds. A model explaining the potency differences of closely related compounds is offered. The data suggest that muscarinic agonists act as functional dopamine antagonists and that they could become a novel treatment of psychotic patients.
Asunto(s)
Antipsicóticos/síntesis química , Antagonistas de Dopamina/síntesis química , Agonistas Muscarínicos/síntesis química , Tiadiazoles/síntesis química , Animales , Antipsicóticos/química , Antipsicóticos/farmacología , Antipsicóticos/toxicidad , Reacción de Prevención/efectos de los fármacos , Encéfalo/metabolismo , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacología , Antagonistas de Dopamina/toxicidad , Evaluación Preclínica de Medicamentos , Técnicas In Vitro , Inyecciones Subcutáneas , Masculino , Ratones , Modelos Moleculares , Conformación Molecular , Actividad Motora/efectos de los fármacos , Agonistas Muscarínicos/química , Agonistas Muscarínicos/farmacología , Agonistas Muscarínicos/toxicidad , Ratas , Ratas Sprague-Dawley , Salivación/efectos de los fármacos , Estereoisomerismo , Relación Estructura-Actividad , Tiadiazoles/química , Tiadiazoles/farmacología , Tiadiazoles/toxicidad , Temblor/inducido químicamenteRESUMEN
(5R,6R)6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3 .2.1]octane (PTAC) is a potent muscarinic receptor ligand with high affinity for central muscarinic receptors and no or substantially less affinity for a large number of other receptors or binding sites including dopamine receptors. The ligand exhibits partial agonist effects at muscarinic M2 and M4 receptors and antagonist effects at muscarinic M1, M3 and M5 receptors. PTAC inhibited conditioned avoidance responding, dopamine receptor agonist-induced behavior and D-amphetamine-induced FOS protein M5 expression in the nucleus accumbens without inducing catalepsy, tremor or salivation at pharmacologically relevant doses. The effect of PTAC on conditioned avoidance responding and dopamine receptor agonist-induced behavior was antagonized by the acetylcholine receptor antagonist scopolamine. The compound selectively inhibited dopamine cell firing (acute administration) as well as the number of spontaneously active dopamine cells (chronic administration) in the limbic ventral tegmental area (A10) relative to the non-limbic substantia nigra, pars compacta (A9). The results demonstrate that PTAC exhibits functional dopamine receptor antagonism despite its lack of affinity for the dopamine receptors and indicate that muscarinic receptor partial agonists may be an important new approach in the medical treatment of schizophrenia.
Asunto(s)
Antipsicóticos/farmacología , Reacción de Prevención/efectos de los fármacos , Encéfalo/efectos de los fármacos , Compuestos Bicíclicos con Puentes/farmacología , Antagonistas de Dopamina/farmacología , Actividad Motora/efectos de los fármacos , Receptores Muscarínicos/efectos de los fármacos , Tiadiazoles/farmacología , Animales , Antiparkinsonianos/farmacología , Apomorfina/farmacología , Encéfalo/metabolismo , Interacciones Farmacológicas , Ligandos , Masculino , Ratones , Antagonistas Muscarínicos/farmacología , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Receptores Muscarínicos/metabolismo , Escopolamina/farmacología , Sistemas de Mensajero Secundario/efectos de los fármacosRESUMEN
Activation of muscarinic m1 receptors which are coupled to the phosphoinositide (PI) second messenger transduction system is the initial objective of cholinergic replacement therapy in Alzheimer's disease. Thus, we evaluated the ability of the selective muscarinic receptor agonist (SMRA) xanomeline to stimulate in vivo phosphoinositide (PI) hydrolysis and compared it to a number of direct acting muscarinic agonists, two cholinesterase inhibitors and a putative m1 agonist/muscarinic m2 antagonist. Using a radiometric technique, it was determined that administration of xanomeline robustly stimulated in vivo PI hydrolysis and the effect was blocked by muscarinic antagonists, demonstrating mediation by muscarinic receptors. The non-selective muscarinic agonists pilocarpine, oxotremorine, RS-86, S-aceclidine, but not the less active isomer R-aceclidine, also effectively stimulated PI hydrolysis in mice. Amongst the putative m1 agonists, thiopilocarpine, hexylthio-TZTP as well as xanomeline effectively stimulated PI hydrolysis, but milameline, WAL 2014, SKB 202026 and PD 142505 did not significantly alter PI hydrolysis. Furthermore, WAL 2014 and SKB 202026 inhibited agonist-induced PI stimulation, suggesting that they act as antagonists at PI-coupled receptors in vivo. The cholinesterase inhibitors, tacrine and physostigmine, and the mixed muscarinic m1 agonist/m2 antagonist LU25-109 did not activate in vivo PI hydrolysis. Xanomeline, hexylthio-TZTP and thiopilocarpine were relatively free of cholinergic side effects, whereas milameline, WAL 2014 and SKB 202026 produced non-selective effects. Therefore, these data demonstrate that xanomeline selectively activates in vivo PI hydrolysis, consistent with activation of biochemical processes involved in memory and cognition and xanomeline's beneficial clinical effects on cognition in Alzheimers patients.
Asunto(s)
Química Encefálica/efectos de los fármacos , Colinérgicos/metabolismo , Agonistas Muscarínicos/farmacología , Fosfatidilinositoles/metabolismo , Piridinas/farmacología , Tiadiazoles/farmacología , Animales , Unión Competitiva/fisiología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Inhibidores de la Colinesterasa/farmacología , Dihidropiridinas/farmacología , Relación Dosis-Respuesta a Droga , Hidrólisis , Hipotermia/inducido químicamente , Iminas/farmacología , Litio/farmacología , Masculino , Ratones , Ratones Endogámicos , Oximas/farmacología , Parasimpaticomiméticos/farmacología , Fisostigmina/farmacología , Pilocarpina/farmacología , Quinuclidinas/farmacología , Ensayo de Unión Radioligante , Salivación/efectos de los fármacos , Tacrina/farmacología , Tetrazoles/farmacología , Temblor/inducido químicamenteRESUMEN
A series of indole-3-carboxamides, indazole-3-carboxamides, and benzimidazolone-3-carboxamides was synthesized and evaluated for antagonist affinity at the 5-HT4 receptor in the rat esophagus. The endo-3-tropanamine derivatives in the indazole and benzimidazolone series possessed greater 5-HT4 receptor affinity than the corresponding indole analogues. 5-HT4 receptor antagonist affinity was further increased by alkylation at N-1 of the aromatic heterocycle. In a series of 1-isopropylindazole-3-carboxamides, replacement of the bicyclic tropane ring system with the monocyclic piperidine ring system or an acyclic aminoalkylene chain led to potent 5-HT4 receptor antagonists. In particular, those systems in which the basic amine was substituted with groups capable of forming hydrogen bonds showed increased 5-HT4 receptor antagonist activity. While some of these compounds displayed high affinity for other neurotransmitter receptors (in particular, 5-HT3, alpha1, and 5-HT2A receptors), as the conformational flexibility of the amine moiety increased, the selectivity for the 5-HT4 receptor also increased. From this series of compounds, we identified LY353433 (1-(1-methylethyl)-N-[2-[4-[(tricyclo[3.3.1.1(3, 7)]dec-1-ylcarbonyl)amino]-1-piperidinyl]ethyl]-1H-indazole-3- carboxamide) as a potent and selective 5-HT4 receptor antagonist with clinically suitable pharmacodynamics.
Asunto(s)
Adamantano/análogos & derivados , Indazoles , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina , Adamantano/administración & dosificación , Adamantano/síntesis química , Adamantano/química , Adamantano/farmacología , Administración Oral , Antagonistas Adrenérgicos alfa/síntesis química , Antagonistas Adrenérgicos alfa/química , Antagonistas Adrenérgicos alfa/farmacología , Animales , Aorta/efectos de los fármacos , Aorta/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Evaluación Preclínica de Medicamentos , Esófago/efectos de los fármacos , Esófago/fisiología , Cobayas , Íleon/efectos de los fármacos , Íleon/fisiología , Técnicas In Vitro , Indazoles/administración & dosificación , Indazoles/síntesis química , Indazoles/química , Indazoles/farmacología , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Ratas , Receptor de Serotonina 5-HT2A , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Receptores de Serotonina 5-HT3 , Receptores de Serotonina 5-HT4 , Antagonistas de la Serotonina/administración & dosificación , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
The acetyl group of the muscarinic agonist aceclidine 4 was replaced by various 1,2,5-thiadiazoles to provide a new series of potent m1 muscarinic agonists 17 and 18. Optimal m1 muscarinic agonist potency was achieved when the 1,2,5-thiadiazole substituent was either a butyloxy, 17d, or butylthio, 18d, group. Although 1,2,5-oxadiazole 37 and pyrazine 39 are iso-pi-electronic with 1,2,5-thiadiazole 17d, both analogues were substantially less active than 17d. Compounds with high muscarinic affinity and/or m1 muscarinic agonist efficacy were also obtained when the 3-oxyquinuclidine moiety of 17d or 18c was replaced by ethanolamines, hydroxypyrrolidines, hydroxyazetidine, hydroxyisotropanes, or hydroxyazanorbornanes. The structure-activity data support the participation of the oxygen or sulfur atom in the substituent on the 1,2,5-thiadiazole in the activation of the m1 receptor. Several of these new 1,2,5-thiadiazoles have m1 agonist efficacy, potency, and selectivity comparable to those of xanomeline 2 in the muscarinic tests investigated.