期刊
JOURNAL OF NEUROCHEMISTRY
卷 158, 期 6, 页码 1217-1222出版社
WILEY
DOI: 10.1111/jnc.15335
关键词
acetylcholinesterase reactivators (AChE reactivators); cholinergic neurotransmission; cholinesterase; nicotinic acetylcholine receptors (nAChRs); pyridinium aldoximes; special issue Cholinergic Mechanisms
资金
- International Union of Biochemistry and Molecular Biology (IUBMB)
This article details novel reactivators that depart from traditional cholinesterase reactivators, focusing on achieving rapid penetration of the central nervous system and reactivation of AChE. These new reactivators should have minimal toxicity, limited inhibitory activity in the absence of organophosphates, and display nucleophilic potential at the conjugated AChE active center.
We detail here distinctive departures from lead classical cholinesterase re-activators, the pyridinium aldoximes, to achieve rapid CNS penetration and reactivation of AChE in the CNS (brain and spinal cord). Such reactivation is consistent with these non-canonical re-activators enhancing survival parameters in both mice and macaques following exposure to organophosphates. Thus, the ideal cholinesterase re-activator should show minimal toxicity, limited inhibitory activity in the absence of an organophosphate, and rapid CNS penetration, in addition to its nucleophilic potential at the target, the conjugated AChE active center. These are structural properties directed to reactivity profiles at the conjugated AChE active center, reinforced by the pharmacokinetic and tissue disposition properties of the re-activator leads. In the case of nicotinic acetylcholine receptor (nAChR) agonists and antagonists, with the many existing receptor subtypes in mammals, we prioritize subtype selectivity in their design. In contrast to nicotine and its analogues that react with panoply of AChR subtypes, the substituted di-2-picolyl amine pyrimidines possess distinctive ionization characteristics reflecting in selectivity for the orthosteric site at the alpha 7 subtypes of receptor. Here, entry to the CNS should be prioritized for the therapeutic objectives of the nicotinic agent influencing aberrant CNS activity in development or in the sequence of CNS ageing (longevity) in mammals, along with general peripheral activities controlling inflammation.
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