α1-Adrenergic Receptors: Insights into Potential Therapeutic Opportunities for COVID-19, Heart Failure, and Alzheimer’s Disease

Abstract

α1-Adrenergic receptors (ARs) are members of the G-Protein Coupled Receptor superfamily and with other related receptors (β and α2), they are involved in regulating the sympathetic nervous system through binding and activation by norepinephrine and epinephrine. Traditionally, α1-AR antagonists were first used as anti-hypertensives, as α1-AR activation increases vasoconstriction, but they are not a first-line use at present. The current usage of α1-AR antagonists increases urinary flow in benign prostatic hyperplasia. α1-AR agonists are used in septic shock, but the increased blood pressure response limits use for other conditions. However, with the advent of genetic-based animal models of the subtypes, drug design of highly selective ligands, scientists have discovered potentially newer uses for both agonists and antagonists of the α1-AR. In this review, we highlight newer treatment potential for α1A-AR agonists (heart failure, ischemia, and Alzheimer’s disease) and non-selective α1-AR antagonists (COVID-19/SARS, Parkinson’s disease, and posttraumatic stress disorder). While the studies reviewed here are still preclinical in cell lines and rodent disease models or have undergone initial clinical trials, potential therapeutics discussed here should not be used for non-approved conditions.

Identification of a Novel Subtype-Selective α1B-Adrenoceptor Antagonist

“…Emerging evidence implicates the importance of α 1 -ARs in the CNS, the cardiovascular, and the immune systems , and places them as potential therapeutic targets to treat various disorders. Subtype-selective α 1 -ARs ligands will be essential to study and fully exploit these receptors as therapeutic targets.…”

“…Subtype-selective α 1 -ARs ligands will be essential to study and fully exploit these receptors as therapeutic targets. Despite decades of research, ligands highly selective for α 1B -AR are still lacking, and the physiological and pathophysiological roles of this receptor subtype remain incompletely understood. , While α 1B -AR is nonselectively targeted (along with α 1A -AR and α 1D -AR) in cardiovascular and genitourinary diseases, its role in other important organs where it is much more abundantly expressed (such as the brain, liver, ovaries, spleen, and kidney) remains to be explored. The discovery of a tool antagonist with greater than 10-fold selectivity for α 1B -AR over α 1A -AR and α 1D -AR would allow researchers to more confidently assign particular physiological actions of catecholamines to α 1B -AR stimulation specifically.…”

Circadian regulation of the immune-hematopoietic system

“…This cellular traffic is functional to maintain an efficient hematopoietic niche as well as to patrol the organism to ensure tissue homeostasis and an appropriate immunological reaction in case of infection. As the circadian control of HSC circulation is effective also when they are mobilized by colony stimulating factors [83], a higher number of HSCs could be harvested by apheresis if it were performed in humans at the beginning of the resting phase rather than in the morning. The number of HSCs is crucial for the success of HSC transplantation, thus this "circadian" procedure could be very useful.…”

Structural basis of agonist specificity of α1A-adrenergic receptor

“…They function through nine distinct human adrenergic receptor (AR) subtypes:and β-type (β 1 , β 2 , and β 3 ) 3,4 . Due to the lack of selective pharmacological agonists for α 1 -ARs, the therapeutic potential of α 1 -ARs has been largely unexplored [5][6][7][8][9] . However, mouse genetic studies with individual gene deletions have demonstrated distinct but overlapping physiological functions of α 1 -AR subtypes in the regulation of blood pressure, cardiac hypertrophy, vascular smooth muscle contraction, neurotransmission, learning and memory, and metabolism [10][11][12][13][14][15][16][17] .…”