3 research outputs found
Furoxans (Oxadiazole‑4<i>N</i>‑oxides) with Attenuated Reactivity are Neuroprotective, Cross the Blood Brain Barrier, and Improve Passive Avoidance Memory
Nitric oxide (NO)
mimetics and other agents capable of enhancing
NO/cGMP signaling have demonstrated efficacy as potential therapies
for Alzheimer’s disease. A group of thiol-dependent NO mimetics
known as furoxans may be designed to exhibit attenuated reactivity
to provide slow onset NO effects. The present study describes the
design, synthesis, and evaluation of a furoxan library resulting in
the identification of a prototype furoxan, <b>5a</b>, which
was profiled for use in the central nervous system. Furoxan <b>5a</b> demonstrated negligible reactivity toward generic cellular
thiols under physiological conditions. Nonetheless, cGMP-dependent
neuroprotection was observed, and <b>5a</b> (20 mg/kg) reversed
cholinergic memory deficits in a mouse model of passive avoidance
fear memory. Importantly, <b>5a</b> can be prepared as a pharmaceutically
acceptable salt and is observed in the brain 12 h after oral administration,
suggesting potential for daily dosing and excellent metabolic stability.
Continued investigation into furoxans as attenuated NO mimetics for
the CNS is warranted
Furoxans (Oxadiazole‑4<i>N</i>‑oxides) with Attenuated Reactivity are Neuroprotective, Cross the Blood Brain Barrier, and Improve Passive Avoidance Memory
Nitric oxide (NO)
mimetics and other agents capable of enhancing
NO/cGMP signaling have demonstrated efficacy as potential therapies
for Alzheimer’s disease. A group of thiol-dependent NO mimetics
known as furoxans may be designed to exhibit attenuated reactivity
to provide slow onset NO effects. The present study describes the
design, synthesis, and evaluation of a furoxan library resulting in
the identification of a prototype furoxan, <b>5a</b>, which
was profiled for use in the central nervous system. Furoxan <b>5a</b> demonstrated negligible reactivity toward generic cellular
thiols under physiological conditions. Nonetheless, cGMP-dependent
neuroprotection was observed, and <b>5a</b> (20 mg/kg) reversed
cholinergic memory deficits in a mouse model of passive avoidance
fear memory. Importantly, <b>5a</b> can be prepared as a pharmaceutically
acceptable salt and is observed in the brain 12 h after oral administration,
suggesting potential for daily dosing and excellent metabolic stability.
Continued investigation into furoxans as attenuated NO mimetics for
the CNS is warranted
Furoxans (Oxadiazole‑4<i>N</i>‑oxides) with Attenuated Reactivity are Neuroprotective, Cross the Blood Brain Barrier, and Improve Passive Avoidance Memory
Nitric oxide (NO)
mimetics and other agents capable of enhancing
NO/cGMP signaling have demonstrated efficacy as potential therapies
for Alzheimer’s disease. A group of thiol-dependent NO mimetics
known as furoxans may be designed to exhibit attenuated reactivity
to provide slow onset NO effects. The present study describes the
design, synthesis, and evaluation of a furoxan library resulting in
the identification of a prototype furoxan, <b>5a</b>, which
was profiled for use in the central nervous system. Furoxan <b>5a</b> demonstrated negligible reactivity toward generic cellular
thiols under physiological conditions. Nonetheless, cGMP-dependent
neuroprotection was observed, and <b>5a</b> (20 mg/kg) reversed
cholinergic memory deficits in a mouse model of passive avoidance
fear memory. Importantly, <b>5a</b> can be prepared as a pharmaceutically
acceptable salt and is observed in the brain 12 h after oral administration,
suggesting potential for daily dosing and excellent metabolic stability.
Continued investigation into furoxans as attenuated NO mimetics for
the CNS is warranted