α_1A-Adrenergic Receptor as a Target for Neurocognition: Cautionary Tale from Nicergoline and Quinazoline...

Decades ago, previous studies that used non-selective ergot derivatives suggested that blockage of the α_1A-adrenergic receptor mildly increased cognition through increased blood flow to the brain due to vasodilation and, thus, could be used as a treatment for dementia. However, further studies indicated that nicergoline was non-specific and hit many different targets. Today, a similar scenario is developing with the use of non-selective α₁-AR antagonists of the quinazoline class, referred to as "osins", as potential treatments for COVID-19/SARS, post-traumatic stress disorder, cancer, and neurodegenerative disorders, such as Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis. While there is extensive evidence of neuroprotection from many clinical trials, the mechanism of action of quinazolines is often not α₁-AR-mediated but keyed to its glycolysis-enhancing effects through activation of the enzyme phosphoglycerate kinase 1 (PGK1). These studies have incorrectly labeled the α_1A-adrenergic receptor as an "old target" to treat Alzheimer's and other neurocognitive diseases, hampering drug development. This review will summarize these and other studies to indicate that activation, not blockage, of norepinephrine's actions, through α_1A-AR, mediates cognitive, memory, and neuroprotective functions that may reverse the progression of neurocognitive diseases.