TB62, A POTENT 5-HT1A SEROTONERGIC FULL AGONIST, ENDOWED WITH DUAL ANTINOCICEPTIVE AND ANXIOLITIC/ANTIDEPRESSANT ACTIVITY

Pain is a physiological experience crucial for self-preservation. It is estimated that more than 30% of the adult population suffers from chronic pain worldwide, generating a huge burden on national and world health services and economies.1 Despite recent advances in pain research, the development of new therapies is challenging, and opioids are still a “gold standard”. Over 15 million people worldwide misuse prescription opioids, therefore, non-addictive treatments for chronic pain are highly needed. Chronic pain can lead to distress, frustration which can contribute to the development or exacerbation of anxiety and depression.2 Conversely, anxiety and depression can lower pain thresholds, intensify pain perception, and increase the risk of developing chronic pain conditions. The serotonergic system (5-HT) plays a critical role in mood state control and endogenous analgesia. Therefore, it represents an excellent target to control both the perceptive and affective components of chronic pain.3 Within a drug discovery project on 5-HT1A ligands, our research group prepared and tested a new series of rigid analogues of a previously identified aralkyl-phenoxyethylammine partial agonist.4 The new compounds were obtained by incorporating the basic nitrogen into a pyrrolidine or piperidine ring, thus leading to the introduction of an additional chiral center. By using stereoselective synthesis, we prepared the four respective enantiomeric couples. Notably, only TB62 enantiomer [4-(S), 2-(R)] showed increased selectivity and full agonist activity, highlighting the role of chirality in the interaction with the 5-HT1A receptor. Preliminary in-vitro studies on mouse spinal cord and hippocampus slices have shown that TB62 activates the 5-HT1A receptors and that its activity is completely antagonized by the 5-HT1A antagonist WAY100635, suggesting a clean profile. Preliminary in-vivo experiments have shown that TB62 does not impair motor coordination and locomotion, an essential prerequisite for a CNS-acting drug, while it exhibited drug efficacy in a mouse model of persistent pain. In parallel, we assessed the anxiolytic and antidepressant potential of TB62. Indeed, this compound was effective in both elevated plus-maze and forced swimming tests. In conclusion, the 5-HT1A full agonist, TB62, could represent an effective, non-opioid therapeutic tool for the treatment of chronic pain and its co-morbidities, such as anxiety and depression. Bibliografia 1. Cohen SP, Vase L, Hooten WM. Chronic pain: an update on burden, best practices, and new advances. Lancet. 2021;397(10289):2082-2097. 2. Kim S, Lee J, Boone D. Protective and Risk Factors at the Intersection of Chronic Pain, Depression, Anxiety, and Somatic Amplification: A Latent Profile Approach. J Pain Res. 2022; 15:1107-1121. 3. Haleem DJ. Targeting Serotonin1A Receptors for Treating Chronic Pain and Depression. Curr Neuropharmacol. 2019;17(12):1098-1108. 4. Prandi A, Franchini S, Manasieva LI, Fossa P, Cichero E, Marucci G, Buccioni M, Cilia A, Pirona L, Brasili L. Synthesis, biological evaluation, and docking studies of tetrahydrofuran- cyclopentanone- and cyclopentanol-based ligands acting at adrenergic α₁- and serotonine 5-HT1A receptors. J Med Chem. 2012;55(1):23-36.