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Molecular Pharmacology

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NEW SYNTHETIC CAFFEINE ANALOGS AS MODULATORS OF THE CHOLINERGIC SYSTEM

Camila Fabiani, Brunella Biscussi, Juan Pablo Munafo, Ana Paula Murray, Jeremias Corradi and Silvia Susana Antollini
Molecular Pharmacology December 30, 2021, MOLPHARM-AR-2021-000415; DOI: https://doi.org/10.1124/molpharm.121.000415
Camila Fabiani
1Instituto de Investigaciones Bioquímicas de Bahía Blanca, Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur y Consejo Nacional de Investigaciones Científicas y Técnicas, Camino La Carrindanga km 7, Argentina
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Brunella Biscussi
2Instituto de Química del Sur, Departamento de Química, Universidad Nacional del Sur y Consejo Nacional de Investigaciones Científicas y Técnicas, Av. Alem 1253, Argentina
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Juan Pablo Munafo
1Instituto de Investigaciones Bioquímicas de Bahía Blanca, Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur y Consejo Nacional de Investigaciones Científicas y Técnicas, Camino La Carrindanga km 7, Argentina
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Ana Paula Murray
2Instituto de Química del Sur, Departamento de Química, Universidad Nacional del Sur y Consejo Nacional de Investigaciones Científicas y Técnicas, Av. Alem 1253, Argentina
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  • For correspondence: silviant@criba.edu.ar
Jeremias Corradi
1Instituto de Investigaciones Bioquímicas de Bahía Blanca, Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur y Consejo Nacional de Investigaciones Científicas y Técnicas, Camino La Carrindanga km 7, Argentina
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  • For correspondence: silviant@criba.edu.ar
Silvia Susana Antollini
1Instituto de Investigaciones Bioquímicas de Bahía Blanca, Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur y Consejo Nacional de Investigaciones Científicas y Técnicas, Camino La Carrindanga km 7, Argentina
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  • For correspondence: silviant@criba.edu.ar
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Abstract

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder. Since cholinergic deficit is a major factor in this disease, two molecular targets for its treatment are the acetylcholinesterase (AChE) and the nicotinic acetylcholine receptors (nAChRs). Given that caffeine is a natural compound that behaves as an AChE inhibitor and as a partial agonist of nAChRs, the aim of this work was to synthetize more potent bifunctional caffeine analogs that modulate these two molecular targets. To this end, a theophylline structure was connected to a pyrrolidine structure through a methylene chain of different lengths (3 to 7 carbon atoms) to give compounds 7-11. All caffeine derivatives inhibited the AChE, of which compound 11 showed the strongest effect. Electrophysiological studies showed that all compounds behave as agonists of the muscle and the neuronal α7 nAChR with greater potency than caffeine. To explore if the different analogs could affect the nAChR conformational state, the nAChR conformational-sensitive probe crystal violet (CrV) was used. Compounds 9 and 10 conduced the nAChR to a different conformational state comparable with a control nAChR desensitized state. Finally, molecular docking experiments showed that all derivatives interacted with both the catalytic and anionic sites of AChE and with the orthosteric binding site of the nAChR. Thus, the new synthetized compounds can inhibit the AChE and activate muscle and α7 nAChRs with greater potency than caffeine, which suggests that they could be useful leaders for the development of new therapies for the treatment of different neurological diseases.

Significance Statement In this work we synthetized caffeine derivatives which can inhibit the AChE and activate both muscle and α7 nAChRs with higher potency than caffeine. These analogs can be divided into two groups: a non-desensitizing and a desensitizing nAChR group. From the nAChR-non desensitizing group, we propose compound 11 as the most interesting analog for further studies since it inhibits AChE with the highest potency and activates the nAChRs in the picomolar range without inducing receptor desensitization.

  • acetylcholinesterase
  • Alzheimer's Disease
  • Drug development
  • electrophysiology
  • Fluorescence techniques
  • ligand docking
  • nicotinic acetylcholine receptors
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 102 (3)
Molecular Pharmacology
Vol. 102, Issue 3
1 Sep 2022
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Caffeine analogs as modulators of the cholinergic system

Camila Fabiani, Brunella Biscussi, Juan Pablo Munafo, Ana Paula Murray, Jeremias Corradi and Silvia Susana Antollini
Molecular Pharmacology December 30, 2021, MOLPHARM-AR-2021-000415; DOI: https://doi.org/10.1124/molpharm.121.000415

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Caffeine analogs as modulators of the cholinergic system

Camila Fabiani, Brunella Biscussi, Juan Pablo Munafo, Ana Paula Murray, Jeremias Corradi and Silvia Susana Antollini
Molecular Pharmacology December 30, 2021, MOLPHARM-AR-2021-000415; DOI: https://doi.org/10.1124/molpharm.121.000415
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