Browsing by Author "Bermudez, Isabel"

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    Aporphine metho salts as neuronal nicotinic acetylcholine receptor blockers
    (2007) Iturriaga-Vasquez, Patricio; Pérez Hernández, Edwin Gregorio; Slater, E. Yvonne; Bermudez, Isabel; Cassels, Bruce K.
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    Neonicotinic analogues: Selective antagonists for α4β2 nicotinic acetylcholine receptors
    (2013) Faundez-Parraguez, Manuel; Farias-Rabelo, Nicolas; Pablo Gonzalez-Gutierrez, Juan; Etcheverry-Berrios, Alvaro; Alzate-Morales, Jans; Adasme-Carreno, Francisco; Varas, Rodrigo; Bermudez, Isabel; Iturriaga-Vasquez, Patricio
    Nicotine is an agonist of nicotinic acetylcholine receptors (nAChRs) that has been extensively used as a template for the synthesis of alpha 4 beta 2-preferring nAChRs. Here, we used the N-methyl-pyrrolidine moiety of nicotine to design and synthesise novel alpha 4 beta 2-preferring neonicotinic ligands. We increased the distance between the basic nitrogen and aromatic group of nicotine by introducing an ester functionality that also mimics acetylcholine (Fig. 2). Additionally, we introduced a benzyloxy group linked to the benzoyl moiety. Although the neonicotinic compounds fully inhibited binding of both [alpha-I-125]bungarotoxin to human alpha 7 nAChRs and [H-3]cytisine to human alpha 4 beta 2 nAChRs, they were markedly more potent at displacing radioligand binding to human alpha 4 beta 2 nAChRs than to alpha 7 nAChRs. Functional assays showed that the neonicotinic compounds behave as antagonists at alpha 4 beta 2 and alpha 4 beta 2 alpha 5 nAChRs. Substitutions on the aromatic ring of the compounds produced compounds that displayed marked selectivity for alpha 4 beta 2 or alpha 4 beta 2 alpha 5 nAChRs. Docking of the compounds on homology models of the agonist binding site at the alpha 4/beta 2 subunit interfaces of alpha 4 beta 2 nAChRs suggested the compounds inhibit function of this nAChR type by binding the agonist binding site. (C) 2013 Elsevier Ltd. All rights reserved.
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    Side Groups Convert the α7 Nicotinic Receptor Agonist Ether Quinuclidine into a Type I Positive Allosteric Modulator
    (2023) Viscarra, Franco; Chrestia, Juan Facundo; Sanchez, Yaima; Perez, Edwin G.; Biggin, Philip C.; Bouzat, Cecilia; Bermudez, Isabel; Lopez, Jhon J.
    The quinuclidine scaffold has been extensively used forthe developmentof nicotinic acetylcholine receptor (nAChR) agonists, with hydrophobicsubstituents at position 3 of the quinuclidine framework providingselectivity for & alpha;7 nAChRs. In this study, six new ligands (4-9) containing a 3-(pyridin-3-yloxy)quinuclidinemoiety (ether quinuclidine) were synthesized to gain a better understandingof the structural-functional properties of ether quinuclidines.To evaluate the pharmacological activity of these ligands, two-electrodevoltage-clamp and single-channel recordings were performed. Only ligand 4 activated & alpha;7 nAChR. Ligands 5 and 7 had no effects on & alpha;7 nAChR, but ligands 6, 8, and 9 potentiated the currents evokedby ACh. Ligand 6 was the most potent and efficaciousof the potentiating ligands, with an estimated EC50 forpotentiation of 12.6 & PLUSMN; 3.32 & mu;M and a maximal potentiationof EC20 ACh responses of 850 & PLUSMN; 120%. Ligand 6 increased the maximal ACh responses without changing thekinetics of the current responses. At the single-channel level, thepotentiation exerted by ligand 6 was evidenced in thelow micromolar concentration range by the appearance of prolongedbursts of channel openings. Furthermore, computational studies revealedthe preference of ligand 6 for an intersubunit site inthe transmembrane domain and highlighted some putative key interactionsthat explain the different profiles of the synthesized ligands. Notably,Met276 in the 15 & PRIME; position of the transmembrane domain 2 almostabolished the effects of ligand 6 when mutated to Leu.We conclude that ligand 6 is a novel type I positiveallosteric modulator (PAM-I) of & alpha;7 nAChR.