NO-SSRIs: Nitric Oxide Chimera Drugs Incorporating a Selective Serotonin Reuptake Inhibitor

Abstract

Hybrid nitrate drugs have been reported to provide NO bioactivity to ameliorate side effects or to provide ancillary therapeutic activity. Hybrid nitrate selective serotonin reuptake inhibitors (NO-SSRIs) were prepared to improve the therapeutic profile of this drug class. A synthetic strategy for use of a thiocarbamate linker was developed, which in the case of NO-fluoxetine facilitated hydrolysis to fluoxetine at pH 7.4 within 7 hours. In cell culture, NO-SSRIs were weak inhibitors of the serotonin transporter, however, in the forced swimming task (FST) in rats, NO-fluoxetine demonstrated classical antidepressant activity. Comparison of NO-fluoxetine, with fluoxetine, and an NO-chimera nitrate developed for Alzheimer’s disease (GT-1061), was made in the step through passive avoidance (STPA) test of learning and memory in rats treated with scopolamine as an amnesic agent. Fluoxetine was inactive, whereas NO-fluoxetine and GT-1061 both restored long-term memory. GT-1061 also produced antidepressant behavior in FST. These data support the potential for NO-SSRIs to overcome the lag in onset of therapeutic action and provide co-therapy of neuropathologies concomitant with depression.

Re-engineering a neuroprotective, clinical drug as a procognitive agent with high in vivo potency and with GABAA potentiating activity for use in dementia

“…Loss is considered to have occurred if the animal remains on its back for more than 30 s. Righting reflex is considered to be regained when the mice were able to successfully right themselves with all four paws touching the floor, twice within 20 s [ 81 ]. Step through passive avoidance (STPA) STPA has been widely used to test long-term working memory and was performed as we have previously described [ 82 – 85 ]. Each animal was given two ip injections: (1) Amnesic agent (scopolamine 1 mg/kg, MK-801 0.1 mg/kg, diazepam 0.5 mg/kg, L-NAME 50 mg/kg) or saline were given 30 min prior to training plus NMZ or saline in the time and delivery method as indicated in Fig.…”

Efficient syntheses of climate relevant isoprene nitrates and (1R,5S)-(−)-myrtenol nitrate

“…Furthermore and in a slightly different context there is significant interest in the pharmaceutical sector in generating structure and function diverse O -nitrate esters for use as in vivo NO-donors. In this context particular emphasis has been placed on developing O -nitrate esters as biologically active agents that act on acetylcholinesterase (AChE), amyloid-βx-42 (Aβ42) aggregation, cyclooxygenase-II (COX2), serotonin reuptake and specific GAG inhibitors [ 21 – 23 ].…”

An NO Donor Approach to Neuroprotective and Procognitive Estrogen Therapy Overcomes Loss of NO Synthase Function and Potentially Thrombotic Risk

“…Furthermore, criteria for training are uniform across all treatment groups. Previously, we have shown NO-donors to reverse cognitive deficits induced by attenuation of cholinergic signaling [50], [51], [52], [53]. In animals administered scopolamine to induce amnesia, all treatments except FDMA and inorganic nitrate induced complete reversal of the memory deficit, with NO-DMA and DMA showing equi-efficacious activity (Fig.…”

“…This training was repeated until latency to enter the dark side reached 300 s. At 24 h post-training, animals were individually placed in the light compartment and the latency to enter the dark compartment was recorded with a 300 s cutoff. Details of this widely used assay of behavior have been discussed previously for NO-donor compounds [53], [54], [55].…”