New Synthetic Caffeine Analogs as Modulators of the Cholinergic System

• Published in: Molecular pharmacology Vol. 101; no. 3; pp. 154 - 167
• Main Authors: Fabiani, Camila, Biscussi, Brunella, Munafó, Juan P, Murray, Ana P, Corradi, Jeremías, Antollini, Silvia S
• Format: Journal Article
• Language: English
• Published: United States 01-03-2022
• Subjects: alpha7 Nicotinic Acetylcholine Receptor - agonists; alpha7 Nicotinic Acetylcholine Receptor - chemistry; alpha7 Nicotinic Acetylcholine Receptor - metabolism; Animals; Caffeine - analogs & derivatives; Caffeine - chemical synthesis; Caffeine - metabolism; Caffeine - pharmacology; Electrophorus; HEK293 Cells; Humans; Molecular Docking Simulation - methods; Protein Structure, Secondary; Torpedo
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/molpharm.121.000415

Alzheimer's disease 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
-
All caffeine derivatives inhibited the AChE, of which compound
showed the strongest effect. Electrophysiological studies showed that all compounds behave as agonists of the muscle and the neuronal
7 nAChR with greater potency than caffeine. To explore whether the different analogs could affect the nAChR conformational state, the nAChR conformational-sensitive probe crystal violet (CrV) was used. Compounds
and
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
7 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 neurologic diseases. SIGNIFICANCE STATEMENT: In this work we synthetized caffeine derivatives which can inhibit acetylcholinesterase and activate both muscle and α7 nicotinic acetylcholine receptors (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
as the most interesting analog for further studies since it inhibits acetylcholinesterase with the highest potency and activates the nAChRs in the picomolar range without inducing receptor desensitization.