RESUMEN
RATIONALE: Disturbances in information processing and cognitive function are key features of schizophrenia. Nicotinic α7 acetylcholine receptors (α7-nAChR) are involved in sensory gating and cognition, thereby representing a viable therapeutic strategy. OBJECTIVES AND METHODS: We investigated the effects of GTS-21, an α7-nAChR partial agonist, on prepulse inhibition (PPI) of acoustic startle in two pharmacologic impairment models in Wistar male rats: NMDA-glutamate receptor antagonism by MK-801 and dopamine receptor agonism by apomorphine. The cognitive effects of GTS-21 were assessed using the object recognition task (ORT) at short (3 h) and long (48 h) delays in Sprague-Dawley male rats. Pharmacological specificity was assessed by methyllycaconitine (MLA) coadministration with GTS-21. RESULTS: In the PPI task, GTS-21 (1-10 mg/kg) alone did not alter the PPI response or startle amplitude. Coadministration of GTS-21 with MK-801 (0.1 mg/kg) or apomorphine (0.5 mg/kg) abolished the pharmacologic-induced PPI impairment as did the antipsychotics clozapine (5.0 mg/kg) and haloperidol (0.3 mg/kg). MK-801 alone increased startle amplitude which was blocked by GTS-21. In the ORT, GTS-21 (0.1-10 mg/kg) reversed the MK-801 (0.08 mg/kg)-induced memory deficit at the 3 h delay and enhanced memory at the 48 h delay, an effect abolished by MLA (0.313-5 mg/kg). CONCLUSIONS: The results extend our preclinical pharmacological understanding of GTS-21 to include the ability of GTS-21 to modulate NMDA-glutamate receptor function, in vivo. Given the role of NMDA-glutamate receptor involvement in schizophrenia, α7-nAChR agonists may represent a novel treatment strategy for the pathophysiological deficits of schizophrenia and other psychiatric disorders.
Asunto(s)
Compuestos de Bencilideno/farmacología , Agonistas Nicotínicos/farmacología , Piridinas/farmacología , Reconocimiento en Psicología/efectos de los fármacos , Reflejo de Sobresalto/efectos de los fármacos , Filtrado Sensorial/efectos de los fármacos , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Animales , Apomorfina/farmacología , Clozapina/farmacología , Cognición/efectos de los fármacos , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas del GABA/farmacología , Haloperidol/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Receptores de N-Metil-D-Aspartato , Receptores Nicotínicos/fisiologíaRESUMEN
Neuronal nicotinic α7 acetylcholine receptors (α7nAChRs) are expressed primarily in the brain and are implicated in modulating many cognitive functions (e.g., attention, working and episodic memory). Not surprisingly, much effort has been committed to the development of molecules acting at α7nAChRs as potential therapies for a variety of central nervous system diseases (e.g., Alzheimer's). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide hydrochloride (RG3487) binds potently to the human α7nAChR (K(i) = 6 nM), in which it acts as a partial agonist (63-69% of acetylcholine) as assessed by whole-cell patch-clamp recordings in both oocytes and QM7 cell lines. RG3487 activates human α7nAChRs with an EC(50) of 0.8 µM (oocytes) and 7.7 µM (QM7 cells). RG3487 also exhibits antagonist properties at the serotonin 3 receptor [IC(50) = 2.8 nM (oocytes), 32.7 nM (N1E-115 cells)]. In vivo, RG3487 improved object recognition memory in rats after acute [minimally effective dose (MED) 1.0 mg/kg p.o.] or repeated (10 day) administration at brain and plasma concentrations in the low-nanomolar range. Spatial learning deficits in age-impaired rats were reversed after RG3487 administration (MED: 0.03 mg/kg i.p.) as evaluated in the Morris water maze task. In the prepulse inhibition (PPI) of startle model of sensorimotor gating, RG3487 improved apomorphine-induced deficits in PPI performance (MED: 0.03 mg/kg i.p.) and reversed phencyclidine-induced impairments in an attentional set-shifting model of executive function (MED: ≤0.03 mg/kg i.p.). Cumulative evidence from these studies indicates RG3487 is a novel and potent α7nAChR partial agonist that improves cognitive performance and sensorimotor gating.
Asunto(s)
Compuestos Bicíclicos con Puentes/farmacología , Cognición/fisiología , Agonismo Parcial de Drogas , Indazoles/farmacología , Agonistas Nicotínicos/farmacología , Receptores Nicotínicos/fisiología , Filtrado Sensorial/fisiología , Animales , Unión Competitiva/efectos de los fármacos , Unión Competitiva/fisiología , Línea Celular Tumoral , Cognición/efectos de los fármacos , Femenino , Humanos , Masculino , Ratas , Ratas Endogámicas F344 , Ratas Long-Evans , Ratas Sprague-Dawley , Ratas Wistar , Filtrado Sensorial/efectos de los fármacos , Xenopus laevis , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
Varenicline, a partial alpha4beta2 and full alpha7 nicotinic receptor agonist, has been shown to inhibit nicotine self-administration and nicotine-induced increases in extracellular dopamine in the nucleus accumbens. In the present study, we investigated whether varenicline inhibits nicotine-enhanced electrical brain-stimulation reward (BSR), and if so, which receptor subtypes are involved. Systemic administration of nicotine (0.25-1.0 mg/kg, i.p.) or varenicline (0.03-3 mg/kg, i.p.) produced biphasic effects, with low doses producing enhancement (e.g., decreased BSR threshold), and high doses inhibiting BSR. Pretreatment with low dose (0.03-1.0 mg/kg) varenicline dose-dependently attenuated nicotine (0.25 or 0.5 mg/kg)-enhanced BSR. The BSR-enhancing effect produced by varenicline was blocked by mecamylamine (a high affinity nicotinic receptor antagonist) or dihydro-beta-erythroidine (a relatively selective nicotinic alpha4-containing receptor antagonist), but not methyllycaconitine (a selective alpha7 receptor antagonist), suggesting an effect mediated by activation of alpha4beta2 receptors. This suggestion is supported by findings that the alpha4beta2 receptor agonist SIB-1765F produced a dose-dependent enhancement of BSR, while pretreatment with SIB-1765F attenuated nicotine (0.5 mg/kg)-enhanced BSR. In contrast, the selective alpha7 receptor agonist ARR-17779, altered neither BSR itself nor nicotine-enhanced BSR, at any dose tested. These findings suggest that: 1) varenicline inhibits nicotine-enhanced BSR, supporting its use as a smoking cessation aid; and 2) varenicline-enhanced BSR by itself and varenicline's anti-nicotine effects are mediated by activation of alpha4beta2, but not alpha7, receptors.
Asunto(s)
Benzazepinas/farmacología , Condicionamiento Operante/efectos de los fármacos , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Quinoxalinas/farmacología , Receptores Nicotínicos/metabolismo , Recompensa , Animales , Condicionamiento Operante/fisiología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Estimulación Eléctrica/métodos , Masculino , Haz Prosencefálico Medial/efectos de los fármacos , Haz Prosencefálico Medial/fisiología , Antagonistas Nicotínicos/farmacología , Ratas , Ratas Long-Evans , VareniclinaRESUMEN
An effective treatment for age-related cognitive deficits remains an unmet medical need. Currently available drugs for the symptomatic treatment of Alzheimer's disease or other dementias have limited efficacy. This may be due to their action at only one of the many neurotransmitter systems involved in the complex mechanisms that underlie cognition. An alternative approach would be to target second messenger systems that are utilized by multiple neurotransmitters. Cyclic adenosine monophosphate (cAMP) is a second messenger that plays a key role in biochemical processes that regulate the cognitive process of memory consolidation. Prolongation of cAMP signals can be accomplished by inhibiting phosphodiesterases (PDEs). Eleven PDE families, comprised of more than 50 distinct members, are currently known. This review summarizes the evidence demonstrating that rolipram, a selective inhibitor of cAMP-selective PDE4 enzymes, has positive effects on learning and memory in animal models. These data provide support for the general approach of second messenger modulation as a potential therapy for cognitive dysfunction, and specifically suggest that PDE4 inhibitors may have utility for improving the symptoms of cognitive decline associated with neurodegenerative and psychiatric diseases.
Asunto(s)
Nootrópicos/uso terapéutico , Inhibidores de Fosfodiesterasa/uso terapéutico , Animales , Trastornos del Conocimiento/tratamiento farmacológico , Humanos , Aprendizaje/efectos de los fármacos , Memoria/efectos de los fármacos , Nootrópicos/química , Nootrópicos/farmacología , Inhibidores de Fosfodiesterasa/farmacologíaRESUMEN
A series of N-[(3S)-1-benzylpyrrolidin-3-yl]-(2-thienyl)benzamides 8 has been prepared and found to bind with high affinity to the human D(4) (hD(4)) and 5-HT(2A) receptors. Several compounds displayed selectivity for these receptors versus hD(2) and alpha(1) adrenergic receptors of over 500-fold.
Asunto(s)
Antipsicóticos/química , Antipsicóticos/farmacología , Benzamidas/química , Benzamidas/farmacología , Receptores de Dopamina D4/antagonistas & inhibidores , Antagonistas del Receptor de Serotonina 5-HT2 , Antipsicóticos/síntesis química , Benzamidas/síntesis química , Dopamina/química , Humanos , LigandosRESUMEN
A series of N-(1-benzylpyrrolidin-3-yl)arylbenzamides 8 has been prepared, and their structure-activity relationships studied. Potent ligands selective for human D(4) (hD(4)) over hD(2) and alpha(1) have been identified. One example was determined to be an antagonist in a cAMP assay, with an IC(50) of 1500 nM.
Asunto(s)
Benzamidas/síntesis química , Antagonistas de Dopamina/síntesis química , Antagonistas de los Receptores de Dopamina D2 , Benzamidas/farmacología , Antagonistas de Dopamina/farmacología , Humanos , Receptores de Dopamina D4 , Relación Estructura-ActividadRESUMEN
A series of 3-(2-pyrrolidin-1-ylethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives (2) has been prepared using parallel synthesis techniques, and their structure-activity relationships studied. High affinity human 5-HT(1B/1D) (h5-HT(1B/1D)) ligands have been identified.
Asunto(s)
Indoles/química , Indoles/metabolismo , Piridinas/química , Piridinas/metabolismo , Receptor de Serotonina 5-HT1B/metabolismo , Humanos , Ligandos , Relación Estructura-ActividadRESUMEN
A novel series of highly potent human 5-HT(1D) agonists, dimethyl-[2-[6-substituted-indol-1-yl]-ethyl]-amine, was synthesized. Structure-activity relationship (SAR) investigation revealed 4-[1-(2-dimethylamino-ethyl)-1H-indol-6-yl]-tetrahydro-thiopyran-4-ol, 11b (ALX-2732), as a potent (K(i)=2.4 nM) agonist at the human 5-HT(1D) receptor with good selectivity over the other serotonin receptor subtypes. This compound demonstrated favorable in vitro metabolic stability in human and rat liver microsomes and was found to be orally bioavailable in rats (F(po)=51%).
Asunto(s)
Aminas/síntesis química , Aminas/farmacología , Indoles/síntesis química , Indoles/farmacología , Receptor de Serotonina 5-HT1B/efectos de los fármacos , Agonistas de Receptores de Serotonina/síntesis química , Agonistas de Receptores de Serotonina/farmacología , Administración Oral , Sitios de Unión , Disponibilidad Biológica , Diseño de Fármacos , Humanos , Cinética , Conformación Molecular , Receptor de Serotonina 5-HT1B/química , Receptor de Serotonina 5-HT1B/fisiología , Agonistas de Receptores de Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/química , Relación Estructura-ActividadRESUMEN
A series of (R)-3-(N-methylpyrrolidin-2-ylmethyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole derivatives (2) have been prepared using parallel synthesis, and their structure-activity relationship studied. High affinity human 5-HT(1B/1D) (h5-HT(1B/1D)) ligands have been identified.
Asunto(s)
Piridinas/química , Receptor de Serotonina 5-HT1B/metabolismo , Receptor de Serotonina 5-HT1D/metabolismo , Humanos , Ligandos , Piridinas/síntesis química , Piridinas/metabolismo , Relación Estructura-ActividadRESUMEN
A novel series of 1-(bicyclopiperazinyl)ethylindole and 1-(homopiperazinyl)ethyl-indole derivatives was synthesized and found to be potent and selective 5-HT(7) receptor ligands.