Quinuclidine ether derivatives as novel ligands of the α7 nicotinic receptor

Abstract

The α7 nicotinic acetylcholine receptor is a ligand-gated cation channel expressed in the brain, mainly in cortex and hippocampus, where it contributes to cognition, attention, and working memory. Its reduced activity has been associated to schizophrenia and Alzhei- mer’s disease. α7 is also expressed in non-neuronal cells, such as astrocytes, microglia and lymphocytes, where it plays a role in in- flammation and immunity. Therefore, potentiation of α7 has emerged as a therapeutic strategy for neurological, neurodegenerative and inflammatory disorders. The quinuclidine scaffold was used for the development of nicotinic agonists, with the hydrophobic substituents at position 3 providing selectivity for α7. Here, six new ligands (4–9) containing a 3-(pyridin-3-yloxy)quinuclidine moiety were synthe- sized, and its pharmacological activity upon α7 was evaluated by two-electrode voltage-clamp and single-channel recordings. Only ligand 4 activated α7. Ligands 5 and 7 had no effects on α7, but ligands 6, 8, and 9 potentiated the ACh-currents. Ligand 6 was the most potent and efficacious of the potentiating ligands, with a EC50 of 12.6 ± 3.32 μM and a maximal potentiation of EC20 ACh respons- es of 850 ± 120%. The concentration–response curve of ACh was shifted to the left by 10 μM ligand 6 (control EC50 = 125 ± 25 μM; ACh + ligand 6 EC50 = 96 ± 30 μM; p<0.05). At the single-channel level, the potentiation exerted by 10 μM ligand 6 was evidenced by the appearance of prolonged bursts of channel openings (1.08 ± 0.32 ms) compared to the control (0.38 ± 0.08 ms, p<0.001). The burst duration is the most sensitive parameter to determine potentiation and relates to the efficacy of the modulator. Computational studies revealed the preference of ligand 6 for an intersubunit site in the transmembrane domain and highlighted some putative key interac- tions that explain the different profiles of the synthesized ligands. We conclude that ligand 6 is a novel positive allosteric modulator of α7.-