Quinuclidine ether derivatives as novel ligands of the αlpha7 nicotinic receptor

CHRESTIA, J.F.; VISCARRA, FRANCO; SANCHEZ, YAIMA; PEREZ EDWIN G; BIGGIN, PHILIP C.; BERMUDEZ, ISABEL; BOUZAT, C.

Congreso; REUNIÓN CONJUNTA SAIC SAB AAFE AACYTAl 2023; 2023

The α7 nicotinic acetylcholine receptor is a ligand-gated cationchannel expressed in the brain, mainly in cortex and hippocampus,where it contributes to cognition, attention, and working memory. Itsreduced activity has been associated to schizophrenia and Alzheimer’sdisease. α7 is also expressed in non-neuronal cells, such asastrocytes, microglia and lymphocytes, where it plays a role in inflammationand immunity. Therefore, potentiation of α7 has emergedas a therapeutic strategy for neurological, neurodegenerative andinflammatory disorders. The quinuclidine scaffold was used for thedevelopment of nicotinic agonists, with the hydrophobic substituentsat position 3 providing selectivity for α7. Here, six new ligands (4–9)containing a 3-(pyridin-3-yloxy)quinuclidine moiety were synthesized,and its pharmacological activity upon α7 was evaluated bytwo-electrode voltage-clamp and single-channel recordings. Onlyligand 4 activated α7. Ligands 5 and 7 had no effects on α7, butligands 6, 8, and 9 potentiated the ACh-currents. Ligand 6 was themost potent and efficacious of the potentiating ligands, with a EC50of 12.6 ± 3.32 μM and a maximal potentiation of EC20 ACh responsesof 850 ± 120%. The concentration–response curve of ACh wasshifted to the left by 10 μM ligand 6 (control EC50 = 125 ± 25 μM; ACh+ ligand 6 EC50 = 96 ± 30 μM; p