A three-dimensional database search has been applied to design a series of endo- and exo-3-(pyridin-3-yl)bicyclo[2.2.1]heptan-2-amines as nicotinic receptor ligands. The synthesized compounds were tested in radioligand binding assay on rat cortex against [3H]-cytisine and [3H]-methyllycaconitine to measure their affinity for α4β2* and α7* nicotinic receptors. The new derivatives showed some preference for the α4β2* over the α7* subtype, with their affinity being dependent on the endo/exo isomerism and on the methylation degree of the basic nitrogen. The endo primary amines displayed the lowest Ki values on both receptor subtypes. Selected compounds (1a, 2a, 3a, and 6a) were tested on heterologously expressed α4β2, α7, and α3β2 receptors and on SHSY-5Y cells. Compounds 1a and 2a showed α4β2 antagonistic properties while behaved as full agonists on recombinant α7 and on SHSY5Y cells. On the α3β2 subtype, only the chloro derivative 2a showed full agonist activity and submicromolar potency (EC50 = 0.43 μM). The primary amines described here represent new chemotypes for the α7 and α3* receptor subtypes.

New Rigid Nicotine Analogues, Carrying a Norbornane Moiety, Are Potent Agonists of α7 and α3∗ Nicotinic Receptors / Dina Manetti*† , Alexandra Garifulina‡, Gian Luca Bartolucci , Carla Bazzicalupi§ , Cristina Bellucci†, Niccolò Chiaramonte†, Silvia Dei†, Lorenzo Di Cesare Mannelli∥, Carla Ghelardini∥, Paola Gratteri⊥ , Ekaterina Spirova‡, Irina Shelukhina‡, Elisabetta Teodori†, Katia Varani#, Victor Tsetlin‡, Maria Novella Romanelli†. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - ELETTRONICO. - 62:(2019), pp. 1887-1901. [10.1021/acs.jmedchem.8b01372]

New Rigid Nicotine Analogues, Carrying a Norbornane Moiety, Are Potent Agonists of α7 and α3∗ Nicotinic Receptors

Dina Manetti†
;
Gian Luca Bartolucci;Carla Bazzicalupi§;Cristina Bellucci†;Niccolò Chiaramonte†;Silvia Dei†;Lorenzo Di Cesare Mannelli∥;Carla Ghelardini∥;Paola Gratteri⊥;Elisabetta Teodori†;Katia Varani#;Maria Novella Romanelli†
2019

Abstract

A three-dimensional database search has been applied to design a series of endo- and exo-3-(pyridin-3-yl)bicyclo[2.2.1]heptan-2-amines as nicotinic receptor ligands. The synthesized compounds were tested in radioligand binding assay on rat cortex against [3H]-cytisine and [3H]-methyllycaconitine to measure their affinity for α4β2* and α7* nicotinic receptors. The new derivatives showed some preference for the α4β2* over the α7* subtype, with their affinity being dependent on the endo/exo isomerism and on the methylation degree of the basic nitrogen. The endo primary amines displayed the lowest Ki values on both receptor subtypes. Selected compounds (1a, 2a, 3a, and 6a) were tested on heterologously expressed α4β2, α7, and α3β2 receptors and on SHSY-5Y cells. Compounds 1a and 2a showed α4β2 antagonistic properties while behaved as full agonists on recombinant α7 and on SHSY5Y cells. On the α3β2 subtype, only the chloro derivative 2a showed full agonist activity and submicromolar potency (EC50 = 0.43 μM). The primary amines described here represent new chemotypes for the α7 and α3* receptor subtypes.
2019
62
1887
1901
Dina Manetti*† , Alexandra Garifulina‡, Gian Luca Bartolucci , Carla Bazzicalupi§ , Cristina Bellucci†, Niccolò Chiaramonte†, Silvia Dei†, Lorenzo Di Cesare Mannelli∥, Carla Ghelardini∥, Paola Gratteri⊥ , Ekaterina Spirova‡, Irina Shelukhina‡, Elisabetta Teodori†, Katia Varani#, Victor Tsetlin‡, Maria Novella Romanelli†
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1151478
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