New Approaches to the treatment of Schizophrenia and other Neuropsychiatric Disorders: Targeting alpha2-adrenoceptors

Schizophrenia is a severe mental illness affecting 21 million people worldwide, resulting in cognitive impairments and negative symptoms that impact patients\u27 ability to live a normal life. Almost all current antipsychotic drugs are dopamine D2 antagonists, which largely address only the positive symptoms. Effective treatments for negative symptoms and cognitive deficits remain unmet clinical needs. The alpha2C-adrenoceptor has been highlighted as a promising neuropsychiatric drug target with excellent therapeutic potential to treat affective and cognitive symptoms. Non-selective alpha2-AR antagonism may compromise therapeutic utility; however, selective alpha2C-AR antagonists have demonstrated pro-cognitive, antidepressant and antipsychotic actions in animal models of neuropsychiatric disorders. This study takes a two-fold approach aimed at expanding our understanding of the structural characteristics required for receptor engagement of guanidine-based alpha2-AR ligands. Firstly, a retrospective analysis of hit alpha2-AR ligands developed over the last 20 years within the Rozas group was conducted, a selection of the most pertinent ligands were chosen to be synthesised and submitted for comprehensive pharmacological screening at the National Institute of Mental Health Psychoactive Drug Screening Program in the University of North Carolina, Chapel Hill (USA). A deeper understanding of the receptor engagement profiles exhibited by these compounds informed the design of novel derivatives that may display optimal pharmacological properties to become novel drug candidates for treatment of schizophrenia and other neuropsychiatric disorders. Hence, the influence of subtle structural modifications around the cationic moiety of current hit compounds on their affinity, activity and selectivity at the alpha2-ARs were synthetically explored to elucidate and potentially improve the characteristics needed to impart the desired biological activity. Secondly, the subtype selectivity of some derivatives with structural similarities to known alpha2C-AR ligands were studied in collaboration with Prof. Callado (University of the Basque Country, Spain), the results of which served as a base for the preparation of new derivatives currently awaiting pharmacological evaluation. This work and the resultant outcomes constitute a strong foundation for future expansion and investigation of novel alpha2-AR subtype selective ligands. The extensive receptor profiles compiled herein will serve as guidelines to assist in the development of new molecules with enhanced affinity and selectivity aimed at particular targets within the central nervous system and can be used in the development of drugs to treat a wide range of mental disorders