RESUMEN
α7 nicotinic acetylcholine receptor agonists are promising therapeutic candidates for the treatment of cognitive impairment. As a follow up of our internal medicinal chemistry program we investigated a novel series of α7 nAChR agonists. Starting from molecular docking studies on two series of molecules recently developed in our laboratories, an alternative scaffold was designed attempting to combine the optimal features of these previously identified urea and pyrazole compounds. Based on our previous SAR knowledge and on predicted drug-like properties, a small library was synthesized in parallel manner, affording compounds with excellent α7 nAChR activity, selectivity and preliminary ADME profile.
Asunto(s)
Diseño de Fármacos , Pirazoles/farmacología , Urea/farmacología , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Animales , Permeabilidad de la Membrana Celular/efectos de los fármacos , Perros , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Modelos Moleculares , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Ratas , Ratas Wistar , Relación Estructura-Actividad , Urea/análogos & derivados , Urea/síntesis químicaRESUMEN
α7 Nicotinic acetylcholine receptors (α7 nAChR) represent promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer's disease (AD) and schizophrenia. A medicinal chemistry effort around previously reported compound 1 (SEN15924, WAY-361789) led to the identification of 12 (SEN78702, WYE-308775) a potent and selective full agonist of the α7 nAChR that demonstrated improved plasma stability, brain levels, and efficacy in behavioral cognition models.
Asunto(s)
Encéfalo/efectos de los fármacos , Cognición/efectos de los fármacos , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Agonistas Nicotínicos/farmacología , Piperidinas/farmacología , Pirazoles/farmacología , Receptores Nicotínicos/química , Animales , Células CHO , Calcio/metabolismo , Química Farmacéutica , Cricetinae , Canal de Potasio ERG1 , Humanos , Modelos Moleculares , Agonistas Nicotínicos/síntesis química , Piperidinas/síntesis química , Pirazoles/síntesis química , Ratas , Receptores Nicotínicos/metabolismo , Relación Estructura-Actividad , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
Alpha-7 nicotinic acetylcholine receptors (α7 nAChR) are implicated in the modulation of many cognitive functions such as attention, working memory, and episodic memory. For this reason, α7 nAChR agonists represent promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer's disease (AD) and schizophrenia. A medicinal chemistry effort, around our previously reported chemical series, permitted the discovery of a novel class of α7 nAChR agonists with improved selectivity, in particular against the α3 receptor subtype and better ADME profile. The exploration of this series led to the identification of 5-(4-acetyl[1,4]diazepan-1-yl)pentanoic acid [5-(4-methoxyphenyl)-1H-pyrazol-3-yl] amide (25, SEN15924, WAY-361789), a novel, full agonist of the α7 nAChR that was evaluated in vitro and in vivo. Compound 25 proved to be potent and selective, and it demonstrated a fair pharmacokinetic profile accompanied by efficacy in rodent behavioral cognition models (novel object recognition and auditory sensory gating).
Asunto(s)
Azepinas/síntesis química , Agonistas Nicotínicos/síntesis química , Pirazoles/síntesis química , Receptores Nicotínicos/metabolismo , Administración Oral , Animales , Azepinas/farmacocinética , Azepinas/farmacología , Encéfalo/metabolismo , Calcio/metabolismo , Dominio Catalítico , Línea Celular , Permeabilidad de la Membrana Celular , Cognición/efectos de los fármacos , Perros , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Masculino , Potenciales de la Membrana/efectos de los fármacos , Modelos Moleculares , Agonistas Nicotínicos/farmacocinética , Agonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/síntesis química , Antagonistas Nicotínicos/farmacocinética , Antagonistas Nicotínicos/farmacología , Técnicas de Placa-Clamp , Pirazoles/farmacocinética , Pirazoles/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Long-Evans , Reflejo de Sobresalto/efectos de los fármacos , Relación Estructura-Actividad , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
RATIONALE: α7 nicotinic acetylcholine receptor (nAChR) agonists are proposed as candidate agents for the adjunctive treatment of cognitive deficits associated with schizophrenia. Despite the pursuit of such an approach clinically, it is surprising that the preclinical profile of pro-cognitive agents in conjunction with antipsychotic drugs is currently unexplored. OBJECTIVES: We determined if the memory-enhancing effects of the selective α7 nAChR agonist WYE-103914 were preserved in the presence of the atypical antipsychotic drug risperidone, and if the antipsychotic-like profile of risperidone was preserved in the presence of WYE-103914. METHODS: Using the rat novel object recognition (NOR) paradigm, the maintenance of memory-enhancing activity of the α7 nAChR agonist WYE-103914 in the presence of risperidone was examined. Similarly, in the standard tests of antipsychotic-like activity, apomorphine-induced climbing (AIC) in mice and conditioned avoidance responding (CAR) in rats, the preservation of antipsychotic-like activity of risperidone was evaluated in the presence of WYE-103914. RESULTS: WYE-103914 exhibited memory-enhancing activity in rat NOR, and this effect of WYE-103914 was retained in the presence of risperidone. In AIC, the atypical antipsychotic profile of risperidone was not significantly altered by WYE-103914. In contrast, WYE-103914 moderately potentiated the efficacy profile of risperidone in CAR, an effect that did not appear to be convincingly linked to a pharmacokinetic interaction. CONCLUSIONS: These data underscore the value of a preclinical evaluation of the adjunctive profile of a memory-enhancing agent in combination with antipsychotics and provide further support to augmentation with α7 nAChR agonists to address the cognitive deficits associated with schizophrenia.
Asunto(s)
Trastornos del Conocimiento/tratamiento farmacológico , Piridinas/farmacología , Risperidona/farmacología , Esquizofrenia/tratamiento farmacológico , Urea/análogos & derivados , Animales , Antipsicóticos/farmacología , Reacción de Prevención/efectos de los fármacos , Trastornos del Conocimiento/etiología , Evaluación Preclínica de Medicamentos , Interacciones Farmacológicas , Quimioterapia Combinada , Masculino , Memoria/efectos de los fármacos , Ratones , Ratas , Ratas Long-Evans , Ratas Sprague-Dawley , Receptores Nicotínicos/efectos de los fármacos , Receptores Nicotínicos/metabolismo , Esquizofrenia/fisiopatología , Urea/farmacología , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
Alpha-7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment. We report a series of novel, potent small molecule agonists (4-18) of the alpha7 nAChR deriving from our continuing efforts in the areas of Alzheimer's disease and schizophrenia. One of the compounds of the series containing a urea moiety (16) was further shown to be a selective agonist of the alpha7 nAChR with excellent in vitro and in vivo profiles, brain penetration, and oral bioavailability and demonstrated in vivo efficacy in multiple behavioral cognition models. Structural modifications leading to the improved selectivity profile and the biological evaluation of this series of compounds are discussed.
Asunto(s)
Agonistas Nicotínicos/síntesis química , Agonistas Nicotínicos/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Receptores Nicotínicos/metabolismo , Urea/análogos & derivados , Urea/síntesis química , Urea/farmacología , Administración Oral , Animales , Humanos , Concentración 50 Inhibidora , Masculino , Modelos Moleculares , Agonistas Nicotínicos/administración & dosificación , Agonistas Nicotínicos/farmacocinética , Conformación Proteica , Piridinas/administración & dosificación , Piridinas/farmacocinética , Ratas , Receptores Nicotínicos/química , Relación Estructura-Actividad , Especificidad por Sustrato , Urea/administración & dosificación , Urea/farmacocinética , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
Novel 5-cyclic amine-3-arylsulfonylindazoles were prepared, and several analogues within this class have been identified as high-affinity 5-HT(6) receptor ligands with improved pharmacokinetic and pharmacological properties. One selected example, 18b, showed good brain penetrability and a generally favorable pharmacokinetic profile with procognitive efficacy in the rat novel object recognition assay. The synthesis and structure-activity relationship of this potent class are discussed.
Asunto(s)
Indazoles/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/metabolismo , Sulfonas/metabolismo , Animales , Unión Competitiva , Encéfalo/metabolismo , Conducta Exploratoria/efectos de los fármacos , Habituación Psicofisiológica/efectos de los fármacos , Humanos , Indazoles/química , Indazoles/farmacología , Modelos Químicos , Estructura Molecular , Ratas , Receptor de Serotonina 5-HT2B/química , Receptor de Serotonina 5-HT2B/metabolismo , Receptores de Serotonina/química , Reconocimiento en Psicología/efectos de los fármacos , Antagonistas del Receptor de Serotonina 5-HT2 , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/farmacocinética , Relación Estructura-Actividad , Sulfonas/química , Sulfonas/farmacologíaRESUMEN
Nicotinic acetylcholine receptors (nAChR) have been strongly implicated as therapeutic targets for treating cognitive deficits in disorders such as schizophrenia and Alzheimer's disease (AD). In particular alpha7 and alpha4beta2 subtype-selective nAChR agonists and partial agonists have been developed as potential candidates for the treatment of schizophrenia, cognitive disorders (including Alzheimer's disease), and inflammation. Further development of positive allosteric modulators and antagonists were also recently reported in the literature. In this review we will cover recent developments focused on the above mentioned nAChR subtypes, starting from the most advanced clinical candidate followed by an overview of literature compounds where potency, selectivity, central nervous system access, pharmacological activity and pharmacokinetic properties are disclosed.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/tratamiento farmacológico , Descubrimiento de Drogas , Antagonistas Nicotínicos/farmacología , Receptores Nicotínicos/metabolismo , Esquizofrenia/tratamiento farmacológico , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/metabolismo , Trastornos del Conocimiento/metabolismo , Antagonistas Nicotínicos/uso terapéutico , Esquizofrenia/complicaciones , Esquizofrenia/metabolismo , Relación Estructura-ActividadRESUMEN
1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-pyrrolopyridines were prepared. Binding assays indicated they are 5-HT(6) receptor ligands, among which 6f and 6g showed high affinity for 5-HT(6) receptors with K(i)=3.9 and 1.7 nM, respectively.
Asunto(s)
Piridinas/farmacología , Pirroles/farmacología , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Células HeLa , Humanos , Ligandos , Piridinas/química , Pirroles/química , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/química , Agonistas de Receptores de Serotonina/químicaRESUMEN
C-6 Biarylmethylamino purine derivatives of roscovitine (1) inhibit cyclin dependent kinases and demonstrate potent antiproliferative activity. Replacement of the aryl rings of the C-6 biarylmethylamino group with heterobiaryl rings has provided compounds with significantly improved activity. In particular, derivatives 18 g and 9 c demonstrated 1000-fold and 1250-fold improvements, respectively, in the growth inhibition of HeLa cells compared to roscovitine (1).
Asunto(s)
Antineoplásicos/farmacología , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Purinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Purinas/síntesis química , Purinas/química , Roscovitina , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Alpha 7 nicotinic acetylcholine receptor (alpha(7) nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment associated with a variety of disorders including Alzheimer's disease and schizophrenia. Alpha 7 nAChRs are expressed in brain regions associated with cognitive function, regulate cholinergic neurotransmission and have been shown to be down regulated in both schizophrenia and Alzheimer's disease. Herein we report a novel, potent small molecule agonist of the alpha 7 nAChR, SEN12333/WAY-317538. This compound is a selective agonist of the alpha(7) nAChR with excellent in vitro and in vivo profiles, excellent brain penetration and oral bioavailability, and demonstrates in vivo efficacy in multiple behavioural cognition models. The SAR and biological evaluation of this series of compounds are discussed.
Asunto(s)
Morfolinas/química , Morfolinas/farmacología , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacología , Piridinas/química , Piridinas/farmacología , Receptores Nicotínicos/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Unión Competitiva , Calcio/metabolismo , Línea Celular , Cognición/efectos de los fármacos , Electrofisiología , Humanos , Morfolinas/farmacocinética , Agonistas Nicotínicos/farmacocinética , Piridinas/farmacocinética , Ratas , Ratas Wistar , Esquizofrenia/tratamiento farmacológico , Relación Estructura-Actividad , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
The alpha7 nicotinic acetylcholine receptor (nAChR) is a promising target for treatment of cognitive dysfunction associated with Alzheimer's disease and schizophrenia. Here, we report the pharmacological properties of 5-morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide [SEN12333 (WAY-317538)], a novel selective agonist of alpha7 nAChR. SEN12333 shows high affinity for the rat alpha7 receptor expressed in GH4C1 cells (K(i) = 260 nM) and acts as full agonist in functional Ca(2+) flux studies (EC(50) = 1.6 microM). In whole-cell patch-clamp recordings, SEN12333 activated peak currents and maximal total charges similar to acetylcholine (EC(50) = 12 microM). The compound did not show agonist activity at other nicotinic receptors tested and acted as a weak antagonist at alpha3-containing receptors. SEN12333 treatment (3 mg/kg i.p.) improved episodic memory in a novel object recognition task in rats in conditions of spontaneous forgetting as well as cognitive disruptions induced via glutamatergic [5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); MK-801] or cholinergic (scopolamine) mechanisms. This improvement was blocked by the alpha7-selective antagonist methyllycaconitine, indicating that it is mediated by alpha7 activation. SEN12333 also prevented a scopolamine-induced deficit in a passive avoidance task. In models targeting other cognitive domains, including attention and perceptual processing, SEN12333 normalized the apomorphine-induced deficit of prepulse inhibition. Neuroprotection of SEN12333 was demonstrated in quisqualate-lesioned animals in which treatment with SEN12333 (3 mg/kg/day i.p.) resulted in a significant protection of choline acetyltransferase-positive neurons in the lesioned hemisphere. Cumulatively, our results demonstrate that the novel alpha7 nAChR agonist SEN12333 has procognitive and neuroprotective properties, further demonstrating utility of alpha7 agonists for treatment of neurodegenerative and cognitive disorders.
Asunto(s)
Trastornos del Conocimiento/tratamiento farmacológico , Morfolinas/uso terapéutico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Agonistas Nicotínicos/uso terapéutico , Piridinas/uso terapéutico , Receptores Nicotínicos/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Calcio/metabolismo , Línea Celular , Cognición/efectos de los fármacos , Trastornos del Conocimiento/metabolismo , Humanos , Masculino , Potenciales de la Membrana/efectos de los fármacos , Estructura Molecular , Morfolinas/química , Morfolinas/farmacocinética , Morfolinas/farmacología , Actividad Motora/efectos de los fármacos , Enfermedades Neurodegenerativas/metabolismo , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacocinética , Fármacos Neuroprotectores/farmacología , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacocinética , Agonistas Nicotínicos/farmacología , Técnicas de Placa-Clamp , Unión Proteica , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Long-Evans , Ratas Wistar , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
En 100 cadáveres del anfiteatro de anatomía macroscópica de la Facultad de Medicina de la Universidad de Cartagena, las secciones de morfología y neurologíadisecaron las arterias que irrigan el encéfalo. Se realiza una revisión de la anatomía y la clínica, con las consecuencias que pueden generarse ante la obstrucción de las arterias cerebrales, teniendo en cuenta que estas circunstancias son comunes en nuestra práctica clínica