RESUMEN
Diazaspirocyclic ligands have been synthesized in four steps as selective α4ß2 nicotinic acetylcholine receptor antagonists. Structural assignment of 1-(pyridin-3-yl)-2-spiropyrrolidino-3,2'-1-azabiclo[2.2.1]heptane 2, was confirmed using a combination of NMR experiments on a key intermediate, spirolactam 9. All three target compounds synthesized in this diazaspirocyclic series exhibited high affinity (K(i)<35 nM) at the human α4ß2 nAChR subtype, and very low affinity for the human α7, α3ß4 (ganglion) and α1ß1γδ (muscle) subtypes (K(i)>500 nM).
Asunto(s)
Compuestos Aza/química , Antagonistas Nicotínicos/química , Receptores Nicotínicos/química , Compuestos de Espiro/química , Heptanos/química , Humanos , Ligandos , Espectroscopía de Resonancia Magnética , Antagonistas Nicotínicos/síntesis química , Antagonistas Nicotínicos/metabolismo , Unión Proteica , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Receptores Nicotínicos/metabolismo , Compuestos de Espiro/síntesis química , Compuestos de Espiro/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.
Asunto(s)
Amidas/metabolismo , Receptores Nicotínicos/metabolismo , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Animales , Perros , Relación Dosis-Respuesta a Droga , Haplorrinos , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad Cuantitativa , RatasRESUMEN
The potential for nicotinic ligands with affinity for the α4ß2 or α7 subtypes to treat such diverse diseases as nicotine addiction, neuropathic pain, and neurodegenerative and cognitive disorders has been exhibited clinically for several compounds while preclinical activity in relevant in vivo models has been demonstrated for many more. For several therapeutic programs, we sought nicotinic ligands with various combinations of affinity and function across both subtypes, with an emphasis on dual α4ß2-α7 ligands, to explore the possibility of synergistic effects. We report here the structure-activity relationships (SAR) for a novel series of 7-heteroaryl-3-azabicyclo[3.3.1]non-6-enes and characterize many of the analogues for activity at multiple nicotinic subtypes.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Neuroblastoma/tratamiento farmacológico , Nicotina/farmacología , Receptores Nicotínicos/metabolismo , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Calcio/metabolismo , Células Cultivadas , Electrofisiología , Humanos , Riñón/citología , Riñón/efectos de los fármacos , Ligandos , Estructura Molecular , Subunidades de Proteína , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Diversification of essential nicotinic cholinergic pharmacophoric elements, i.e., cationic center and hydrogen bond acceptor, resulted in the discovery of novel potent α4ß2 nAChR selective agonists comprising a series of N-acyldiazabicycles. Core characteristics of the series are an exocyclic carbonyl moiety as a hydrogen bond acceptor and endocyclic secondary amino group. These features are positioned at optimal distance and with optimal relative spatial orientation to provide near optimal interactions with the receptor. A novel potent and highly selective α4ß2 nAChR agonist 3-(5-chloro-2-furoyl)-3,7-diazabicyclo[3.3.0]octane (56, TC-6683, AZD1446) with favorable pharmaceutical properties and in vivo efficacy in animal models has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions and is currently being progressed to phase 2 clinical trials as a treatment for Alzheimer's disease.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Trastornos del Conocimiento/tratamiento farmacológico , Agonistas Nicotínicos/síntesis química , Receptores Nicotínicos/metabolismo , Animales , Encéfalo/metabolismo , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular , Cricetinae , Cricetulus , Conducta Exploratoria/efectos de los fármacos , Humanos , Masculino , Modelos Moleculares , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacología , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
In an attempt to generate nicotinic acetylcholine receptor (nAChR) ligands selective for the alpha4beta2 and alpha7 subtype receptors we designed and synthesized constrained versions of anabasine, a naturally occurring nAChR ligand. 2-(Pyridin-3-yl)-1-azabicyclo[2.2.2]octane, 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane, and several of their derivatives have been synthesized in both an enantioselective and a racemic manner utilizing the same basic synthetic approach. For the racemic synthesis, alkylation of N-(diphenylmethylene)-1-(pyridin-3-yl)methanamine with the appropriate bromoalkyltetrahydropyran gave intermediates which were readily elaborated into 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane and 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane via a ring opening/aminocyclization sequence. An alternate synthesis of 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane via the alkylation of N-(1-(pyridin-3-ylethylidene)propan-2-amine has also been achieved. The enantioselective syntheses followed the same general scheme, but utilized imines derived from (+)- and (-)-2-hydroxy-3-pinanone. Chiral HPLC shows that the desired compounds were synthesized in >99.5% ee. X-ray crystallography was subsequently used to unambiguously characterize these stereochemically pure nAChR ligands. All compounds synthesized exhibited high affinity for the alpha4beta2 nAChR subtype ( K i < or = 0.5-15 nM), a subset bound with high affinity for the alpha7 receptor subtype ( K i < or = 110 nM), selectivity over the alpha3beta4 (ganglion) receptor subtype was seen within the 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane series and for the muscle (alpha1betagammadelta) subtype in the 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane series.
Asunto(s)
Compuestos Bicíclicos con Puentes/síntesis química , Piridinas/síntesis química , Quinuclidinas/síntesis química , Receptores Nicotínicos/química , Animales , Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos con Puentes/metabolismo , Ligandos , Estructura Molecular , Piridinas/química , Piridinas/metabolismo , Quinuclidinas/química , Quinuclidinas/metabolismo , Ratas , Receptores Nicotínicos/metabolismo , EstereoisomerismoRESUMEN
Novel bicyclic alpha-amino acids, exo and endo-1-azabicyclo[2.2.1]heptane-2-carboxylic acid, 1-azabicyclo[2.2.1]heptane-7-carboxylic acid, and 1-azabicyclo[3.2.2]nonane-2-carboxylic acid have been readily synthesized for the generation of neuronal nicotinic receptor ligands. Alkylation of glycine-derived Schiff bases or nitroacetates with cyclic ether electrophiles, followed by acid-induced ring opening and cyclization in NH4OH, allowed for the preparation of substantial quantities of the three tertiary bicyclic alpha-amino acids.
Asunto(s)
Aminoácidos/síntesis química , Compuestos Bicíclicos con Puentes/síntesis química , Aminoácidos/química , Compuestos Bicíclicos con Puentes/química , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Estructura Molecular , EstereoisomerismoRESUMEN
We have recently provided evidence for nicotine-induced complex formation between the alpha7 nicotinic acetylcholine receptor (nAChR) and the tyrosine-phosphorylated enzyme Janus kinase 2 (JAK2) that results in subsequent activation of phosphatidylinositol-3-kinase (PI-3-K) and Akt. Nicotine interaction with the alpha7 nAChR inhibits Abeta (1-42) interaction with the same receptor, and the Abeta (1-42)-induced apoptosis is prevented through nicotine-induced activation of JAK2. These effects can be shown by measuring markers of cytotoxicity, including the cleavage of the nuclear protein poly(ADP-ribose) polymerase (PARP), the induction of caspase 3, or cell viability. In this study, we found that 2-(3-pyridyl)-1-azabicyclo[3.2.2]nonane (TC-1698), a novel alpha7-selective agonist, exerts neuroprotective effects via activation of the JAK2/PI-3K cascade, which can be neutralized through activation of the angiotensin II (Ang II) AT(2) receptor. Vanadate not only augmented the TC-1698-induced tyrosine phosphorylation of JAK2 but also blocked the Ang II neutralization of TC-1698-induced neuroprotection against Abeta (1-42)-induced cleavage of PARP. Furthermore, when SHP-1 was neutralized via antisense transfection, the Ang II inhibition of TC-1698-induced neuroprotection against Abeta (1-42) was prevented. These results support the main hypothesis that states that JAK2 plays a central role in the nicotinic alpha7 receptor-induced activation of the JAK2-PI-3K cascade in PC12 cells, which ultimately contribute to nAChR-mediated neuroprotection. Ang II inhibits this pathway through the AT(2) receptor activation of the protein tyrosine phosphatase SHP-1. This study supports central and opposite roles for JAK2 and SHP-1 in the control of apoptosis and alpha7-mediated neuroprotection in PC12 cells.