Furoxans (Oxadiazole-4N-oxides) with Attenuated Reactivity are Neuroprotective, Cross the Blood Brain Barrier, and Improve Passive Avoidance Memory

Abstract

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, 5a, which was profiled for use in the central nervous system. Furoxan 5a demonstrated negligible reactivity toward generic cellular thiols under physiological conditions. Nonetheless, cGMP-dependent neuroprotection was observed, and 5a (20 mg/kg) reversed cholinergic memory deficits in a mouse model of passive avoidance fear memory. Importantly, 5a 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.

Design, Synthesis and Biological Evaluation of Nitrate Derivatives of Sauropunol A and B as Potent Vasodilatory Agents

“…Nitric oxide has long been considered as a critical cellular signaling molecule related to different chemical and biological responses within the human body [1,2,3]. Since NO is extensively involved in numerous physiological and pathological processes, the manipulation of its biosynthesis as well as the administration of NO-releasing agents has emerged to be an effective way for the treatment of various human diseases such as cardiovascular disorders [4], neurodegeneration [5,6], inflammation [7], cancer [8,9,10,11], microorganism infection [12,13] and some immune diseases [14,15]. As a common method for drug design, molecular hybridization was usually used to introduce NO-releasing part, also known as NO donor, into an existing chemical entity.…”

Design, Synthesis, and in vitro Evaluation of P2X7 Antagonists

“…[39] Scheme 1. Reagents and conditions: (a) Despite the reported tautomerism, [39] only the indicated isomer 20 was obtained under these conditions, [40] which was used for the synthesis of analogues…”

Pharmacokinetics and pharmacodynamics of nitric oxide mimetic agents

“…In animals, NO mimetic efficacy was hypothesized based on ability to reverse scopolamine induced deficits in contextual fear memory using step-trough passive avoidance (STPA). The ability of agents which enhance NO/cGMP signaling to reverse cholinergic memory deficits in STPA is well characterized and has been benchmarked for nitrates, sGC activators, protein kinase G (PKG, a downstream kinase of cGMP) activators, and several phosphodiesterase inhibitors (PDEi; PDE is responsible for breaking down cGMP) [36][37][38][39][40][41][42].…”

“…Preference for thiophilic reactivity is associated with the electronic character of the furoxan ring system [54]. Manipulation of electron density within the furoxan ring via ring substitution pattern, allows modulation or 'tuning' NO release, potentially yielding attenuated slow onset NO mimetics [55]. Over the past 30 years, furoxan research has been largely centralized within the laboratory of Alberto Gasco at the University of Torino.…”

“…The NO/sGC pathway is inhibited by oligomeric amyloid beta (Aβ42) [38,78], making the NO/sGC pathway an attractive drug target. NO/cGMP signaling is required for long-term potentiation (LTP)-i.e., sustained strengthening of synaptic signal [79,80].…”