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The coronavirus disease 2019 (COVID-19) vaccines are the essential public health intervention to confer immunity against severe acute respiratory syndrome coronavirus 2, while decreasing the risks of severe COVID-19 disease, hospitalizations, and death associated with natural infection. Public health experts agree that the public health interventions of social distancing and face coverings will only be able to successfully curtail the COVID-19 pandemic in the United States when combined with the highly effective COVID-19 vaccines. The risk for severe COVID-19 is higher in Americans with highly prevalent metabolic and cardiovascular chronic conditions as well as vulnerable demographics, such as minorities and pregnant women. Unfortunately, experience with past unethical health practices can influence current vaccine confidence in people of color and women of childbearing age. Pharmacists are well-positioned in myriad health care settings across the nation to listen to these concerns and have the conversations necessary to increase vaccine confidence. Similar to effective roles that pharmacists have had in other health prevention efforts such as smoking cessation, pharmacists possess the motivational interviewing skills to guide patients from the "precontemplation" to the "action" stages of health behavior change. This nonjudgmental, mutual understanding will help identify the individual factors influencing vaccine decision-making and bring us closer to achieving "community immunity."

Rational design of lead compounds targeting monoamine transporters (MATs) is critical to developing novel therapeutics to treat psychiatric disorders including depression and substance abuse. A 3-D dopamine transporter (DAT) computer model was used to virtually screen a commercially available small molecules library for high DAT affinity drug-like compounds. One hit, coded "MI-4," inhibited human dopamine, norepinephrine, and serotonin transporters in vitro. In vivo administration in mice induced robust, dose-dependent antidepressant-like behaviors in learned helplessness models (tail suspension and forced swim tests). Moreover, chronic administration (21 day, 10 mg/kg, bid) reduced drinking latencies comparable to fluoxetine (10 mg/kg, bid) in the novelty-induced hypophagia test, which requires chronic treatment to produce antidepressant-like effects. MI-4 (10 mg/kg, bid) produced rapid (three-day) antidepressant-like effects in the social-avoidance test following 10 days of social-defeat stress. Unlike ketamine, chronic administration of MI-4 increased social interaction scores while improving resiliency to the mood-altering effects of stress to over 70%. Importantly, MI-4 exhibited minimal abuse liability in behavioral and neurological models (conditioned place preference and dopamine in vivo microdialysis). MI-4 was found to be Ro-25-6981, an ifenprodil analog and reputed NMDA antagonist. The data suggest that Ro-25-6981, previously known for rapid-acting glutamatergic antidepressant actions, may also functionally inhibit monoamine reuptake and produces sustained antidepressant effects in vivo. This demonstrates, as proof of principle, the viability of combining these mechanisms to produce rapid and sustained antidepressant-like effects. Overall, these findings suggest MAT computational model-based virtual screening is a viable method for identifying antidepressant lead compounds of unique scaffold.

Ligand virtual screening (VS) using the vestibular binding pocket of a 3-D monoamine transporter (MAT) computational model followed by in vitro pharmacology led to the identification of a human serotonin transporter (hSERT) inhibitor with modest affinity (hSERT K(i) = 284 nM). Structural comparison of this VS-elucidated compound, denoted MI-17, to known SERT ligands led to the rational design and synthesis of DJLDU-3-79, a molecular hybrid of MI-17 and dual SERT/5-HT(1A) receptor antagonist SSA-426. Relative to MI-17, DJLDU-3-79 displayed 7-fold improvement in hSERT binding affinity and a 3-fold increase in [(3)H]-serotonin uptake inhibition potency at hSERT/HEK cells. This hybrid compound displayed a hSERT:hDAT selectivity ratio of 50:1, and a hSERT:hNET (human norepinephrine transporter) ratio of200:1. In mice, DJLDU-3-79 decreased immobility in the tail suspension test comparable to the SSRI fluvoxamine, suggesting that DJLDU-3-79 may possess antidepressant properties. This proof of concept study highlights MAT virtual screening as a powerful tool for identifying novel inhibitor chemotypes and chemical fragments for rational inhibitor design.

A continuing challenge in treating depression is therapeutic delay and resistance to available treatments. Hence, the growing interest in developing antidepressants (AD) with rapid onset (hours to days) and novel mechanisms of action. For example, the glutamatergic antagonist ketamine has rapid AD efficacy but is limited by poor bioavailability, short duration of effect, and potential for abuse. Here we report MI-4, identified through virtual screening targeting the human dopamine transporter, inhibited the human monoamine transporters of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in vitro. In vivo administration of MI-4 in mice induced robust, dose-dependent AD-like behaviors in acute models of learned helplessness (tail suspension test and forced swim test). Moreover, 21-day administration of MI-4 reduced drinking latency times comparable to fluoxetine in the novelty-induced hypophagia test, which requires chronic treatment to produce AD effects. Interestingly, like ketamine, MI-4 also exh...