RESUMEN
The interaction of 13-desmethylspirolide C (SPX-desMe-C) and gymnodimine with several nicotinic and muscarinic acetylcholine receptors was investigated. Interaction at the muscarinic receptors was minimal. At nicotinic receptors, both SPX-desMe-C and gymnodimine displayed greatest affinity for the α7 receptor. The rank order for binding affinity (Ki) for SPX-desMe-C was α7 > α6ß3ß4α5 >> rat α3ß4, α1ßγδ > α4ß4, human α3ß4 > human α4ß2 > rat α4ß2 and for gymnodimine was α7, α6ß3ß4α5 > rat α3ß4 > human α3ß4, α4ß4 > rat α4ß2, human α4ß2 > α1ßγδ. Both molecules antagonized agonist-induced nicotinic responses. The antagonism rank order of potency (IC(50)) for SPX-desMe-C was α7 > low sensitivity (LS) α4ß2 > human α3ß4 > high sensitivity (HS) α4ß2, α1ßγδ > α4ß4 > rat α3ß4 and for gymnodimine was LS α4ß2 > human α3ß4 > α7 > HS α4ß2 > α4ß4 > rat α3ß4 > α1ßγδ. Neither gymnodimine nor SPX-desMe-C antagonism could be surmounted by increasing concentrations of nicotine. To elucidate the nature of this insurmountable blockade, we carried out homology modelling and molecular docking studies of both ligands with α7 nAChR. Their very high binding affinity results from very tight hydrophobic enclosures, in addition to previously reported hydrogen-bond and cation-π interactions. Also, the higher the hydrophilic surface area of the binding site of nAChRs, the weaker the binding affinity of both ligands. Together these results show the targets of action are nicotinic and define these marine toxins as additional tools to advance our understanding regarding interactions between antagonists and the nAChR ligand binding domain.
Asunto(s)
Compuestos Heterocíclicos con 3 Anillos/metabolismo , Hidrocarburos Cíclicos/metabolismo , Iminas/metabolismo , Toxinas Marinas/metabolismo , Receptores Muscarínicos/metabolismo , Receptores Nicotínicos/metabolismo , Compuestos de Espiro/metabolismo , Animales , Sitios de Unión/fisiología , Unión Competitiva/fisiología , Femenino , Humanos , Ratas , Ratas Sprague-DawleyRESUMEN
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
The first total synthesis of the natural product 3-hydroxy-11-norcytisine (1), structurally related to cytisine (2), a benchmark ligand at neuronal nicotinic acetylcholine receptors (NNRs), has been achieved. The synthesis permits the unambiguous confirmation of the structure originally proposed for 1 and has enabled initial biological characterization of 1 and its related compounds against NNRs.