RESUMEN
Individuals with schizophrenia smoke at high frequency relative to the general population. Despite the harmful effects of cigarette smoking, smoking among schizophrenic patients improves cognitive impairments not addressed or worsened by common neuroleptics. Varenicline, a nonselective neuronal nicotinic receptor (NNR) agonist and full agonist of 5-HT3A receptors, helps reduce smoking among schizophrenic patients. To determine whether varenicline also improves a cognitive symptom of schizophrenia, namely, impaired sensory gating, a transgenic mouse with schizophrenia, th-fgfr1(tk-), was used. Varenicline dose-dependently increased prepulse inhibition (PPI) of the startle response, a measure of sensory gating, in th-fgfr1(tk-) mice and normalized PPI deficits relative to nontransgenic controls. With the highest dose (10 mg/kg), however, there was a robust elevation of PPI and startle response, as well as reduced exploratory behavior in the open field and elevated plus maze. Pretreatment with the nonspecific NNR antagonist mecamylamine attenuated the exaggerated PPI response and, similar to the 5-HT3A receptor antagonist ondansetron, it prevented the reduction in exploratory behavior. Collectively, these results indicate that varenicline at low-to-moderate doses may be beneficial against impaired sensory gating in schizophrenia; however, higher doses may induce anxiogenic effects, which can be prevented with antagonists of NNRs or 5-HT3A receptors.
Asunto(s)
Benzazepinas/farmacología , Conducta Exploratoria/efectos de los fármacos , Agonistas Nicotínicos/farmacología , Quinoxalinas/farmacología , Filtrado Sensorial/efectos de los fármacos , Animales , Benzazepinas/administración & dosificación , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/etiología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Transgénicos , Agonistas Nicotínicos/administración & dosificación , Quinoxalinas/administración & dosificación , Receptores de Serotonina 5-HT3/efectos de los fármacos , Receptores de Serotonina 5-HT3/metabolismo , Reflejo de Sobresalto/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/fisiopatología , Agonistas del Receptor de Serotonina 5-HT3/farmacología , Antagonistas del Receptor de Serotonina 5-HT3/farmacología , VareniclinaRESUMEN
Abnormal involuntary movements or dyskinesias are a serious complication of long-term l-DOPA treatment of Parkinson's disease, for which there are few treatment options. Accumulating preclinical data show that nicotine decreases l-DOPA-induced dyskinesias (LIDs), suggesting that it may be a useful antidyskinetic therapy for Parkinson's disease. Here, we investigated whether nicotinic acetylcholine receptor (nAChR) agonists reduced LIDs in nonhuman primates. We first tested the nonselective nAChR agonist 1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine (varenicline), which offers the advantage that it is approved by the U.S. Food and Drug Administration for use in humans. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys (n = 23) were first administered l-DOPA/carbidopa (10/2.5 mg/kg) twice daily 5 days/week until stably dyskinetic. Oral varenicline (0.03-0.10 mg/kg) decreased LIDs â¼50% compared with vehicle-treated monkeys, whereas nicotine treatment (300 µg/ml in drinking water) reduced LIDs by 70% in a parallel group of animals. We next tested the selective α4ß2*/α6ß2* nAChR agonist TC-8831 [3-cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane] on LIDs in the same set of monkeys after a 10-week washout. We also tested TC-8831 in another set of MPTP-lesioned monkeys (n = 16) that were nAChR drug-naïve. Oral TC-8831 (0.03-0.3 mg/kg) reduced LIDs in both sets by 30-50%. After a washout period, repeat TC-8831 dosing led to a greater decline in LIDs (60%) in both sets of monkeys that was similar to the effect of nicotine. Tolerance to any nAChR drug did not develop over the course of the study (3-4 months). NAChR drug treatment did not worsen parkinsonism or cognitive ability. These data suggest that nAChR agonists may be useful for the management of dyskinesias in l-DOPA-treated Parkinson's disease patients.
Asunto(s)
Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/toxicidad , Agonistas Nicotínicos/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Discinesia Inducida por Medicamentos/fisiopatología , Femenino , Masculino , Nicotina/uso terapéutico , Enfermedad de Parkinson/fisiopatología , Receptores Nicotínicos/fisiología , SaimiriRESUMEN
We have carried out computational studies on interactions of diazabicyclic amide analogs with α4ß2 nAChR using homology modeling, docking and pharmacophore elucidation techniques. We have found alternative ligand binding modes in most cases. All these diverse poses exhibit the quintessential hydrogen-bonding interaction between the ligand basic nitrogen and the backbone carbonyl oxygen atom of the highly conserved Trp-149. This hydrogen bond was always found to be shorter than the one contracted by the ligand carbonyl group and a second hydrogen-bond made by the cationic center with Tyr-93 of the principal face of the protein. In most of the poses observed, cation-π interactions involved three aromatic residues located in the principal face of the protein: Trp-149, Tyr-190 and Tyr-197. The latter amino acid residue appears to often donate a hydrogen-bond to the ligand carbonyl oxygen atom. We also describe two rings of alternative receptor-based hydrogen-bond donor features equidistantly separated from the carbonyl oxygen of the highly conserved Trp-149 approximately by 5 and 8Å, respectively. These findings could be exploited to design diverse and selective novel chemical libraries for the treatment of diseases and conditions where the α4ß2 nAChR is disrupted, such as Alzheimer disease, Parkinson's disease and l-dopa-induced dyskinesia (LID).
Asunto(s)
Compuestos de Azabiciclo/farmacología , Receptores Nicotínicos/metabolismo , Compuestos de Azabiciclo/síntesis química , Compuestos de Azabiciclo/química , Sitios de Unión/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Compounds containing a quinuclidine scaffold are promising drug candidates for pharmacological management of the central nervous system (CNS) pathologies implicating nAChRs. We have carried out binding affinity and in-silico docking studies of arylmethylene quinuclidine-like derivatives at the α4ß2 receptor using in-vitro receptor binding assay and comparative modeling, respectively. We found that introducing a hydrogen-bond acceptor into the 3-benzylidene quinuclidine derivative resulted in a 266-fold increase in binding affinity and confers agonism properties. By contrast, addition of a phenyl group to 3-benzylidene quinuclidine derivative only results in an 18-fold increase in binding affinity, without conferring agonism. We also found that docking into the orthosteric binding site of the α4ß2 nAChR is consistent with the fact that the basic nitrogen atom donates a hydrogen-bond to the carbonyl group of the highly conserved Trp-149, as initially observed by Dougherty and co-workers.(1) The experimentally-observed trend in binding affinity at both α4ß2 and α3ß4 nAChRs was accurately and independently confirmed by quantum mechanics (QM)-polarized docking. The reduction in binding affinity to the α3ß4 subtype primarily results from a dampening of both coulombic and cation-π interactions.
Asunto(s)
Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacología , Quinuclidinas/química , Quinuclidinas/farmacología , Receptores Nicotínicos/metabolismo , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Unión ProteicaRESUMEN
We have carried out a comparative study between docking into homology models and Bayesian categorization, as applied to virtual screening of nicotinic ligands for binding at various nAChRs subtypes (human and rat α4ß2, α7, α3ß4, and α6ß2ß3). We found that although results vary with receptor subtype, Bayesian categorization exhibits higher accuracy and enrichment than unconstrained docking into homology models. However, docking accuracy is improved when one sets up a hydrogen-bond (HB) constraint between the cationic center of the ligand and the main-chain carbonyl group of the conserved Trp-149 or its homologue (a residue involved in cation-π interactions with the ligand basic nitrogen atom). This finding suggests that this HB is a hallmark of nicotinic ligands binding to nAChRs. Best predictions using either docking or Bayesian were obtained with the human α7 nAChR, when 100 nM was used as cutoff for biological activity. We also found that ligand-based Bayesian-derived enrichment factors and structure-based docking-derived enrichment factors highly correlate to each other. Moreover, they correlate with the mean molecular fractional polar surface area of actives ligands and the fractional hydrophobic/hydrophilic surface area of the binding site, respectively. This result is in agreement with the fact that hydrophobicity strongly contributes in promoting nicotinic ligands binding to their cognate nAChRs.
Asunto(s)
Simulación del Acoplamiento Molecular , Receptores Nicotínicos/química , Bibliotecas de Moléculas Pequeñas/química , Interfaz Usuario-Computador , Receptor Nicotínico de Acetilcolina alfa 7/química , Animales , Teorema de Bayes , Sitios de Unión , Descubrimiento de Drogas , Ensayos Analíticos de Alto Rendimiento , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Unión Proteica , Ratas , Homología Estructural de Proteína , Relación Estructura-Actividad , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Receptor Nicotínico de Acetilcolina alfa 7/antagonistas & inhibidoresRESUMEN
In recent years the etiopathology of a number of debilitating diseases such as type 2 diabetes, arthritis, atherosclerosis, psoriasis, asthma, cystic fibrosis, sepsis, and ulcerative colitis has increasingly been linked to runaway cytokine-mediated inflammation. Cytokine-based therapeutic agents play a major role in the treatment of these diseases. However, the temporospatial changes in various cytokines are still poorly understood and attempts to date have focused on the inhibition of specific cytokines such as TNF-α. As an alternative approach, a number of preclinical studies have confirmed the therapeutic potential of targeting alpha7 nicotinic acetylcholine receptor-mediated anti-inflammatory effects through modulation of proinflammatory cytokines. This "cholinergic anti-inflammatory pathway" modulates the immune system through cholinergic mechanisms that act on alpha7 receptors expressed on macrophages and immune cells. If the preclinical findings translate into human efficacy this approach could potentially provide new therapies for treating a broad array of intractable diseases and conditions with inflammatory components.
Asunto(s)
Citocinas/metabolismo , Inflamación/metabolismo , Modelos Moleculares , Agonistas Nicotínicos/metabolismo , Receptores Nicotínicos/metabolismo , Artritis/complicaciones , Asma/complicaciones , Colitis Ulcerosa/complicaciones , Fibrosis Quística/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Humanos , Inflamación/tratamiento farmacológico , Inflamación/etiología , Modelos Biológicos , Estructura Molecular , Agonistas Nicotínicos/química , Enfermedad de Parkinson/complicaciones , Psoriasis/complicaciones , Sepsis/complicaciones , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
Inflammatory disorders are characterized by the influx of immune cells into the vascular wall of veins and/or arteries in response to stimuli such as oxidized-LDL and various pathogens. These factors stimulate the local production of pro-inflammatory cytokines by macrophages and other cells that promote various inflammatory diseases such as atherosclerosis, Crohn's, Alzheimer's and diabetes. Numerous cytokines play a significant role in this process, though tumor necrosis factor (TNF) and various interleukins are thought to be among the most important regulators. These proinflammatory cytokines promote the above-described diseases by inducing endothelial cell dysfunction. In this brief commentary we will discuss some of the latest advances and discoveries in the treatment of these inflammatory diseases, making use of alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists.
Asunto(s)
Inflamación/prevención & control , Inflamación/fisiopatología , Agonistas Nicotínicos/farmacología , Receptores Nicotínicos/metabolismo , Animales , Citocinas/inmunología , Células Endoteliales/efectos de los fármacos , Humanos , Interleucinas/metabolismo , Macrófagos/metabolismo , Ratones , Agonistas Nicotínicos/química , Agonistas Nicotínicos/uso terapéutico , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
Type 2 diabetes has become a pervasive public health problem. The etiology of the disease has not been fully defined but appears to involve abnormalities in peripheral and central nervous system pathways, as well as prominent inflammatory components. Because nicotinic acetylcholine receptors (nAChRs) are known to interact with anti-inflammatory pathways and have been implicated in control of appetite and body weight, as well as lipid and energy metabolism, we examined their role in modulating biological parameters associated with the disease. In a model of type 2 diabetes, the homozygous leptin-resistant db/db obese mouse, we measured the effects of a novel alpha7 nAChR-selective agonist [5-methyl-N-[2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]thiophene-2-carboxamide (TC-7020)] on body mass, glucose and lipid metabolism, and proinflammatory cytokines. Oral administration of TC-7020 reduced weight gain and food intake, reduced elevated glucose and glycated hemoglobin levels, and lowered elevated plasma levels of triglycerides and the proinflammatory cytokine tumor necrosis factor-alpha. These changes were reversed by the alpha7-selective antagonist methyllycaconitine, confirming the involvement of alpha7 nAChRs. Prevention of weight gain, decreased food intake, and normalization of glucose levels were also blocked by the Janus kinase 2 (JAK2) inhibitor alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide (AG-490), suggesting that these effects involve linkage of alpha7 nAChRs to the JAK2-signal transducer and activator of transcription 3 signaling pathway. The results show that alpha7 nAChRs play a central role in regulating biological parameters associated with diabetes and support the potential of targeting these receptors as a new therapeutic strategy for treatment.
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Agonistas Nicotínicos/farmacología , Obesidad/prevención & control , Quinuclidinas/farmacología , Receptores Nicotínicos/metabolismo , Tiofenos/farmacología , Aumento de Peso/efectos de los fármacos , Animales , Unión Competitiva , Glucemia/metabolismo , Línea Celular , Clonación Molecular , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Tipo 2/sangre , Fenómenos Electrofisiológicos , Metabolismo Energético/efectos de los fármacos , Femenino , Humanos , Ligandos , Metabolismo de los Lípidos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Estructura Molecular , Agonistas Nicotínicos/química , Obesidad/sangre , Obesidad/metabolismo , Oocitos/metabolismo , Técnicas de Placa-Clamp , Quinuclidinas/química , Ratas , Receptores de Leptina/genética , Receptores Nicotínicos/biosíntesis , Receptores Nicotínicos/fisiología , Tiofenos/química , Factor de Necrosis Tumoral alfa/sangre , Xenopus laevis , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
(+/-)-Mecamylamine is a racemic mixture of a widely used brain-permeant noncompetitive inhibitor of muscle-type and neuronal nicotinic receptors (NNRs). The present studies evaluated whether the stereoisomers of this drug show different profiles for inhibition of the high-sensitivity (HS) and low-sensitivity (LS) isoforms of the human alpha4beta2 NNR subtype expressed in subclonal human epithelial 1 cells. We found that at low concentrations (micromolar range), TC-5214 [S-(+)-mecamylamine] was more effective than TC-5213 [R-(-)-mecamylamine] in inhibiting the LS alpha4beta2 NNRs. In addition, we demonstrated that TC-5214 potentiated and TC-5213 inhibited agonist-induced activation of HS alpha4beta2 NNRs. The stereoselectivity of mecamylamine enantiomers at HS and LS alpha4beta2 receptors demonstrates that TC-5214 is the preferred stereoisomer for selective activation of HS, whereas it is more effective in suppressing LS receptor function. This feature could be relevant to therapeutic applications where such a selective mechanism of action is required.
Asunto(s)
Regulación Alostérica/efectos de los fármacos , Mecamilamina/farmacología , Receptores Nicotínicos/efectos de los fármacos , Regulación Alostérica/fisiología , Fenómenos Biofísicos/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Células Epiteliales , Humanos , Mecamilamina/química , Músculos/citología , Músculos/efectos de los fármacos , Músculos/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Receptores Nicotínicos/metabolismo , EstereoisomerismoRESUMEN
Direct comparison of pyridine versus pyrimidine substituents on a small but diverse set of ligands indicates that the pyrimidine substitution has the potential to enhance affinity and/or functional activity at alpha6 subunit-containing neuronal nicotinic receptors (NNRs) and decrease activation of ganglionic nicotinic receptors, depending on the scaffold. The ramifications of this structure-activity relationship are discussed in the context of the design of small molecules targeting smoking cessation.
Asunto(s)
Química Farmacéutica/métodos , Receptores Nicotínicos/química , Cese del Hábito de Fumar/métodos , Animales , Dopamina/metabolismo , Diseño de Fármacos , Humanos , Cinética , Ligandos , Ratones , Modelos Químicos , Nicotina/química , Enfermedad de Parkinson/tratamiento farmacológico , Unión Proteica , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
A number of studies have confirmed the potential for neuronal nicotinic acetylcholine receptor (NNR)-mediated neuroprotection and, more recently, its anti-inflammatory effects. The mechanistic overlap between these pathways and the ubiquitous effects observed following diverse insults suggest that NNRs modulate fundamental pathways involved in cell survival. These results have wide-reaching implications for the design of experimental therapeutics that regulate inflammatory and anti-apoptotic responses through NNRs and represent an initial step toward understanding the benefits of novel therapeutic strategies for the management of central nervous system disorders that target neuronal survival and associated inflammatory processes.
Asunto(s)
Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Receptores Nicotínicos/efectos de los fármacos , Animales , Antiinflamatorios/farmacología , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Enfermedades del Sistema Nervioso Central/fisiopatología , Sistemas de Liberación de Medicamentos , Evaluación Preclínica de Medicamentos , Humanos , Inflamación/fisiopatología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Receptores Nicotínicos/metabolismoRESUMEN
(E)-5-(Pyrimidin-5-yl)-1,2,3,4,7,8-hexahydroazocine (TC299423) is a novel agonist for nicotinic acetylcholine receptors (nAChRs). We examined its efficacy, affinity, and potency for α6ß2∗ (α6ß2-containing), α4ß2∗, and α3ß4∗ nAChRs, using [125I]-epibatidine binding, whole-cell patch-clamp recordings, synaptosomal 86Rb+ efflux, [3H]-dopamine release, and [3H]-acetylcholine release. TC299423 displayed an EC50 of 30-60 nM for α6ß2∗ nAChRs in patch-clamp recordings and [3H]-dopamine release assays. Its potency for α6ß2∗ in these assays was 2.5-fold greater than that for α4ß2∗, and much greater than that for α3ß4∗-mediated [3H]-acetylcholine release. We observed no major off-target binding on 70 diverse molecular targets. TC299423 was bioavailable after intraperitoneal or oral administration. Locomotor assays, measured with gain-of-function, mutant α6 (α6L9'S) nAChR mice, show that TC299423 elicits α6ß2∗ nAChR-mediated responses at low doses. Conditioned place preference assays show that low-dose TC299423 also produces significant reward in α6L9'S mice, and modest reward in WT mice, through a mechanism that probably involves α6(non-α4)ß2∗ nAChRs. However, TC299423 did not suppress nicotine self-administration in rats, indicating that it did not block nicotine reinforcement in the dosage range that was tested. In a hot-plate test, TC299423 evoked antinociceptive responses in mice similar to those of nicotine. TC299423 and nicotine similarly inhibited mouse marble burying as a measure of anxiolytic effects. Taken together, our data suggest that TC299423 will be a useful small-molecule agonist for future in vitro and in vivo studies of nAChR function and physiology.
RESUMEN
Agonists of nicotinic acetylcholine receptors (nAChRs) produce long-lasting cognitive effects in animal models and humans. The duration of these cognitive effects can outlast the presence of the agonists in the system, and the persistence of cognitive enhancement is increased further by repeated exposure. The basis for this discrepancy appears be the cellular and systemic mechanisms of learning and memory. Agonists of nAChRs induce long-term potentiation (LTP), which is a strengthening of synaptic connections that is associated with learning and memory formation. Some of the cellular effects of nAChR agonists overlap with the known cellular mechanisms of LTP, including long-lasting increases in intracellular concentrations of Ca2+, activation of second-messenger systems and transcription factors, elevated levels of gene products and enhanced neurotransmitter release. A better understanding of this phenomenon might shed new light on the role of nAChR systems in memory formation and retrieval.
Asunto(s)
Trastornos del Conocimiento/tratamiento farmacológico , Agonistas Nicotínicos/uso terapéutico , Cognición/efectos de los fármacos , Trastornos del Conocimiento/psicología , Humanos , Potenciación a Largo Plazo , Nicotina/farmacología , Agonistas Nicotínicos/farmacocinéticaRESUMEN
The potential therapeutic benefit of nicotinic ligands in a variety of neurodegenerative pathologies involving the CNS has energized research efforts to develop nicotinic acetylcholine receptor (nAChR) subtype-selective ligands (Bencherif and Schmitt, 2005). In particular, there has been a concerted effort to develop nicotinic compounds with selectivity for CNS nAChRs as potential pharmaceutical tools in the management of these disorders. Clinical and experimental data demonstrate a central role for alpha7 and alpha4beta2 nAChRs in cognitive function, sensory processing, mood, and neuroprotection (Bencherif and Schmitt, 2005; Buccafusco et al., 2005). The development of safe alpha7-selective ligands has been hampered by their lack of discrimination with hERG channels and 5-HT3 receptors. We have developed a number of compounds that display nanomolar affinity to the alpha7 and/or the alpha4beta2 receptor. Investigation of alpha7 functional activity showed a full range of activities from antagonists to full agonists without any significant activity at the human 5-HT3 receptor, P450 isozymes, hERG channels, or in the AMES test. Our findings demonstrate that potent and highly selective nAChR ligands can be designed.
Asunto(s)
Colinérgicos/uso terapéutico , Receptores Nicotínicos/fisiología , Animales , Colinérgicos/farmacología , Cognición/efectos de los fármacos , Cognición/fisiología , Maleato de Dizocilpina/uso terapéutico , Humanos , Ligandos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Receptores Nicotínicos/efectos de los fármacosRESUMEN
To date, the primary treatments for Alzheimer's disease with proven efficacy have been acetylcholinesterase inhibitors that prevent the hydrolysis of acetylcholine (ACh) in the synaptic cleft, thereby prolonging its activity. Although these agents have some benefit in alleviating cognitive impairment, they have limited clinical utility because of insufficient efficacy and marginal tolerability. Within the last decade, there has been much experimental support for the use of therapeutics that directly target nicotinic ACh receptors (nAChRs) to improve cognitive function and slow neurodegenerative disease progression. These findings have spurred considerable research efforts to develop ligands selective for nAChRs, such as ABT-418 (Arneric et al., 1995), SIB-1553 (Bontempi et al., 2001), TC-2403 (Lippiello et al., 1996), and TC-2559 (Bencherif et al., 2000). There is abundant evidence that nAChR modulators have the potential to alleviate cognitive impairment in demented states. In addition to improving cognitive function, a large body of research implicates a role for nAChRs in neuroprotection, suggesting potential for disease modification. An impact of nAChR agonists on disease progression would provide an advantage over currently available treatments for memory loss. The profile of previous nAChR-targeted clinical candidates has not been adequate to warrant further development owing to poor oral bioavailability, side effects, and/or lack of efficacy. Thus, a challenge in nAChR drug design and development has been the reduction of undesirable effects that result from activity at specific nAChRs in the CNS and PNS, including cardiovascular toxicity, emesis, seizures, and hypothermia.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Cognición/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Receptores Nicotínicos/fisiología , Administración Oral , Enfermedad de Alzheimer/psicología , Animales , Humanos , Memoria/efectos de los fármacos , Receptores Nicotínicos/efectos de los fármacosRESUMEN
We showed recently that nicotine activates the growth-promoting enzyme Janus kinase 2 (JAK2) in PC12 cells and that preincubation of these cells with the JAK2-specific inhibitor AG-490 blocked the nicotine-induced neuroprotection against beta-amyloid (1-42) [Abeta (1-42)]. These results provided direct evidence for linkage between JAK2 and the alpha7 nicotinic acetylcholine receptor-induced neuroprotection in PC12 cells. We also showed that preincubation with angiotensin II (Ang II), functioning via the angiotensin II type 2 (AT2) receptor, blocked both the nicotine-induced activation of JAK2 and its neuroprotection against Abeta (1-42). Recently growth-inhibitory effects of the AT2 receptor have been reported to be mediated by the activation of protein tyrosine phosphatases (PTPases) and that AT2 receptor stimulation is associated with a rapid activation of the PTPase SHP-1 (the cytoplasmic tyrosine phosphatase that contains Src homology 2 domains), a negative regulator of JAK2 signaling. Therefore, the potential biological significance of AT2 receptor-induced effects on both the nicotine-induced activation of JAK2 and its neuroprotection against Abeta (1-42) led us to investigate whether SHP-1 activation could be involved in this process. We found that Ang II induced the activation of SHP-1 and that an antisense against SHP-1 not only augmented the nicotine-induced tyrosine phosphorylation of JAK2 but also blocked the Ang II neutralization of the nicotine-induced neuroprotection. These results demonstrate that nicotine-induced tyrosine phosphorylation of JAK2 and neuroprotection against Abeta (1-42) in PC12 cells are blocked by Ang II via AT2 receptor-induced activation of SHP-1.
Asunto(s)
Péptidos beta-Amiloides/farmacología , Angiotensina II/farmacología , Fármacos Neuroprotectores/farmacología , Nicotina/farmacología , Fragmentos de Péptidos/farmacología , Proteínas Tirosina Fosfatasas/metabolismo , Proteínas Proto-Oncogénicas , Péptidos beta-Amiloides/antagonistas & inhibidores , Animales , Apoptosis , Antagonismo de Drogas , Activación Enzimática/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular , Janus Quinasa 2 , Células PC12 , Fragmentos de Péptidos/antagonistas & inhibidores , Feocromocitoma/tratamiento farmacológico , Feocromocitoma/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 6 , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Ratas , Receptor de Angiotensina Tipo 2/metabolismoRESUMEN
The structural heterogeneity, the ubiquity of anatomical distribution, and the demonstrated modulation of biological functions is consistent with the view that nicotinic cholinergic signaling plays a key regulatory role in the brain and influences a number of neuronal processes including sensory processing, motor activity, and cognitive function. It has become evident that perturbation of nicotinic cholinergic neurotransmission can result in diverse CNS pathologies providing the potential for therapeutic intervention in a number of neurodegenerative, neuropsychiatric and neurological disorders. This review will provide a status on the rationale for neuronal therapies targeting neuronal nicotinic receptors (nAChRs) and discusses the multifaceted beneficial effects than can be achieved through manipulation of cholinergic pharmacology. Recent advances and issues relating to rational drug design based on the structure of acetylcholine binding protein are discussed.
Asunto(s)
Enfermedades del Sistema Nervioso/tratamiento farmacológico , Neuronas/efectos de los fármacos , Agonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/farmacología , Receptores Nicotínicos/efectos de los fármacos , Animales , Diseño de Fármacos , Humanos , Trastornos Mentales/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Agonistas Nicotínicos/uso terapéutico , Antagonistas Nicotínicos/uso terapéuticoRESUMEN
Twenty years ago the alpha7 nicotinic acetylcholine receptor (nAChR) was thought to be vestigial with little biological relevance, but in recent years it has emerged as a functional target with ubiquitous localization and biological roles. In the last decade more than two thousand manuscripts have been published unraveling the multi-dimensional complexity of this target, the heterogeneity of its genetic variants, the spectrum of transducing signals, and the critical roles it plays in pivotal biological functions in the protection and maturation of neurons and stems cells, immune and inflammatory responses, sensory gating, mnemonic and attentional processes. In addition research and development of novel drugs has also promoted an intense debate on the role of activation, desensitization, ß -amyloid oligomers, glutamate, and alpha7 nAChR, in cognition, neuronal survival, and neurodegeneration. The initial alpha7 nAChRs transducing enzyme, aptly named after Janus the two-faced roman deity for crossroads and gateways, reflects the dichotomy of reports on alpha7 nAChRs in promoting neuronal survival and cognitive processes, or as the target of ß- amyloid oligomers to destabilize neuronal homeostasis leading to an irreversible neurochemical demise and dementia. It is therefore important to understand the functional neural bases of alpha7 nAChRs-mediated improvement of biological functions. The promise of alpha7 nAChR-directed drugs has already recently translated into proof-of-concept in controlled clinical trials but the full promise of this target(s) will be fully unraveled when its impact on neuronal health and survival is tested in controlled long-term clinical trials of disease progression.
Asunto(s)
Enfermedades del Sistema Nervioso Central/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Animales , Enfermedades del Sistema Nervioso Central/genética , Humanos , Receptor Nicotínico de Acetilcolina alfa 7/genéticaRESUMEN
Neuronal nicotinic acetylcholine receptors (NNRs) of the α7 subtype have been shown to contribute to the release of dopamine in the nucleus accumbens. The site of action and the underlying mechanism, however, are unclear. Here we applied a circuit modeling approach, supported by electrochemical in vivo recordings, to clarify this issue. Modeling revealed two potential mechanisms for the drop in accumbal dopamine efflux evoked by the selective α7 partial agonist TC-7020. TC-7020 could desensitize α7 NNRs located predominantly on dopamine neurons or glutamatergic afferents to them or, alternatively, activate α7 NNRs located on the glutamatergic afferents to GABAergic interneurons in the ventral tegmental area. Only the model based on desensitization, however, was able to explain the neutralizing effect of coapplied PNU-120596, a positive allosteric modulator. According to our results, the most likely sites of action are the preterminal α7 NNRs controlling glutamate release from cortical afferents to the nucleus accumbens. These findings offer a rationale for the further investigation of α7 NNR agonists as therapy for diseases associated with enhanced mesolimbic dopaminergic tone, such as schizophrenia and addiction.
Asunto(s)
Dopamina/metabolismo , Núcleo Accumbens/fisiología , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/fisiología , Colinérgicos/farmacología , Ácido Glutámico/metabolismo , Isoxazoles/farmacología , Masculino , Modelos Neurológicos , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Núcleo Accumbens/efectos de los fármacos , Compuestos de Fenilurea/farmacología , Quinuclidinas/farmacología , Ratas Sprague-Dawley , Sinapsis/efectos de los fármacos , Sinapsis/fisiología , Tiofenos/farmacología , Ácido gamma-Aminobutírico/metabolismoRESUMEN
We have synthesized a novel series of compounds, 3,6-diazabicyclo[3.1.1]heptane-3-carboxamides, targeting both the α4ß2 and α6/α3ß2ß3 nAChRs. Members of the obtained chemical library are partial or full agonists at both the high sensitivity (α4)2(ß2)3 and α6/α3ß2ß3 nAChRs. 3-(Cyclopropylcarbonyl)-3,6-diazabicyclo[3.1.1]heptane (TC-8831 or compound 7 herein) demonstrated a safe in vitro pharmacological profile and the potential for reducing or preventing L-dopa-induced dyskinesias (LID) in several in vivo animal models [1-4]. In vivo metabolism studies in rat and in vitro metabolism studies in liver microsomes from human, rat, dog and monkey showed TC-8831 to be relatively stable. In vivo pharmacokinetic analysis in the rat confirmed brain penetration, with an average brain:plasma ratio of approximately 0.3 across time points from 0.5 to 4 h. Docking into homology models predicted alternative binding modes for TC-8831 and highlighted the importance of the cationic center, hydrogen-bond acceptor, and hydrophobic aliphatic features in promoting binding affinity to both nAChRs. Pharmacophore elucidation confirmed the importance of these key interactions. QSAR modeling suggested that binding affinity is primarily driven by ligand shape, relative positive charge distribution onto the molecular surface, and molecular flexibility. Of the two subtypes, ligand binding to α6ß2ß3 appears to be more sensitive to bulkiness and flexibility.