Marta Quadri1, Almin Silnović2, Carlo Matera2, Nicole A Horenstein3, Clare Stokes4, Marco De Amici2, Roger L Papke4, Clelia Dallanoce5. 1. Department of Pharmaceutical Sciences, Medicinal Chemistry Section "Pietro Pratesi, University of Milan, Via L. Mangiagalli 25, 20133, Milan, Italy; Department of Pharmacology and Therapeutics, University of Florida, P.O. Box 100267, Gainesville, FL, 32610-0267, USA. 2. Department of Pharmaceutical Sciences, Medicinal Chemistry Section "Pietro Pratesi, University of Milan, Via L. Mangiagalli 25, 20133, Milan, Italy. 3. Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville, FL, 32611-7200, USA. 4. Department of Pharmacology and Therapeutics, University of Florida, P.O. Box 100267, Gainesville, FL, 32610-0267, USA. 5. Department of Pharmaceutical Sciences, Medicinal Chemistry Section "Pietro Pratesi, University of Milan, Via L. Mangiagalli 25, 20133, Milan, Italy. Electronic address: clelia.dallanoce@unimi.it.
Abstract
α7 nicotinic acetylcholine receptors (nAChRs) are relevant therapeutic targets for a variety of disorders including neurodegeneration, cognitive impairment, and inflammation. Although traditionally identified as an ionotropic receptor, the α7 subtype showed metabotropic-like functions, mainly linked to the modulation of immune responses. In the present work, we investigated the structure-activity relationships in a set of novel α7 ligands incorporating the 5-(quinuclidin-3-ylmethyl)-1,2,4-oxadiazole scaffold, i.e. derivatives 21a-34a and 21b-34b, aiming to identify the structural requirements able to preferentially trigger one of the two activation modes of this receptor subtype. The new compounds were characterized as partial and silent α7 nAChR agonists in electrophysiological assays, which allowed to assess the contribution of the different groups towards the final pharmacological profile. Overall, modifications of the selected structural backbone mainly afforded partial agonists, among them tertiary bases 27a-33a, whereas additional hydrogen-bond acceptor groups in permanently charged ligands, such as 29b and 31b, favored a silent desensitizing profile at the α7 nAChR.
α7 nicotinic acetylcholine receptors (n class="Gene">nAChRs) are relevant therapeutic targets for a variety of disorders including neurodegeneration, cognitive impairment, and inflammation. Although traditionally identified as an ionotropic receptor, the α7 subtype showed metabotropic-like functions, mainly linked to the modulation of immune responses. In the present work, we investigated the structure-activity relationships in a set of novel α7 ligands incorporating the 5-(quinuclidin-3-ylmethyl)-1,2,4-oxadiazole scaffold, i.e. derivatives 21a-34a and 21b-34b, aiming to identify the structural requirements able to preferentially trigger one of the two activation modes of this receptor subtype. The new compounds were characterized as partial and silent α7 nAChR agonists in electrophysiological assays, which allowed to assess the contribution of the different groups towards the final pharmacological profile. Overall, modifications of the selected structural backbone mainly afforded partial agonists, among them tertiary bases 27a-33a, whereas additional hydrogen-bond acceptor groups in permanently charged ligands, such as 29b and 31b, favored a silent desensitizing profile at the α7 nAChR.
Authors: Maria Chiara Pismataro; Nicole A Horenstein; Clare Stokes; Marta Quadri; Marco De Amici; Roger L Papke; Clelia Dallanoce Journal: Eur J Med Chem Date: 2020-07-28 Impact factor: 6.514
Authors: Michael Sebastian Salazar Intriago; Roberta Piovesana; Alessandro Matera; Marilena Taggi; Rita Canipari; Cinzia Fabrizi; Claudio Papotto; Carlo Matera; Marco De Amici; Clelia Dallanoce; Ada Maria Tata Journal: Molecules Date: 2021-12-18 Impact factor: 4.411