{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T13:59:32Z","timestamp":1764079172684,"version":"build-2065373602"},"reference-count":26,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2016,4,14]],"date-time":"2016-04-14T00:00:00Z","timestamp":1460592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Integrated Drug Discovery Technology Platform of National Science and Technology Major Projects","award":["(2012ZX09301003-001-006)"],"award-info":[{"award-number":["(2012ZX09301003-001-006)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Ampakine compounds have been shown to reverse opiate-induced respiratory depression by activation of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. However, their pharmacological exploitations are hindered by low blood-brain barrier (BBB) permeability and limited brain distribution. Here, we explored whether thiamine disulfide prodrugs with the ability of \u201clock-in\u201d can be used to solve these problems. A series of thiamine disulfide prodrugs 7a\u20137f of ampakine compound LCX001 was synthesized and evaluated. The trials in vitro showed that prodrugs 7e, 7d, 7f possessed a certain stability in plasma and quickly decomposed in brain homogenate by the disulfide reductase. In vivo, prodrug 7e decreased the peripheral distribution of LCX001 and significantly increased brain distribution of LCX001 after i.v. administration. This compound showed 2.23- and 3.29-fold greater increases in the AUC0-t and MRT0-t of LCX001 in brain, respectively, than did LCX001 itself. A preliminary pharmacodynamic study indicated that the required molar dose of prodrug 7e was only one eighth that of LCX001 required to achieve the same effect in mice. These findings provide an important reference to evaluate the clinical outlook of ampakine compounds.<\/jats:p>","DOI":"10.3390\/molecules21040488","type":"journal-article","created":{"date-parts":[[2016,4,14]],"date-time":"2016-04-14T12:37:04Z","timestamp":1460637424000},"page":"488","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Design, Synthesis and Biological Evaluation of Brain-Targeted Thiamine Disulfide Prodrugs of Ampakine Compound LCX001"],"prefix":"10.3390","volume":"21","author":[{"given":"Dian","family":"Xiao","sequence":"first","affiliation":[{"name":"Laboratory of Computer-Aided Drug Design &amp; Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fan-Hua","family":"Meng","sequence":"additional","affiliation":[{"name":"Laboratory of Computer-Aided Drug Design &amp; Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Dai","sequence":"additional","affiliation":[{"name":"Laboratory of Computer-Aided Drug Design &amp; Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zheng","family":"Yong","sequence":"additional","affiliation":[{"name":"Laboratory of Computer-Aided Drug Design &amp; Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin-Qiu","family":"Liu","sequence":"additional","affiliation":[{"name":"Laboratory of Computer-Aided Drug Design &amp; Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin-Bo","family":"Zhou","sequence":"additional","affiliation":[{"name":"Laboratory of Computer-Aided Drug Design &amp; Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Song","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Computer-Aided Drug Design &amp; Discovery, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2016,4,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1067\/msg.20011.118495","article-title":"Pain treatment in the perioperative period","volume":"38","author":"Swarm","year":"2001","journal-title":"Curr. Probl. Surg."},{"key":"ref_2","first-page":"6","article-title":"When opioid analgesia kills","volume":"4","author":"Desrosiers","year":"2006","journal-title":"Perspect. Infirm."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.2165\/00003088-200645110-00001","article-title":"Fatal respiratory depression after multiple intravenous morphine injections","volume":"45","author":"Dudziak","year":"2006","journal-title":"Clin. Pharmacokinet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1097\/ALN.0b013e3181c38c25","article-title":"Incidence, reversal, and prevention of opioid-induced respiratory depression","volume":"112","author":"Dahan","year":"2010","journal-title":"Anesthesiology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"198","DOI":"10.18773\/austprescr.2015.069","article-title":"Opioid prescribing pitfalls: Medicolegal and regulatory issues","volume":"38","author":"Jammal","year":"2015","journal-title":"Aust. Prescr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1111\/acem.12485","article-title":"Emergency medical services naloxone access: A national systematic legal review","volume":"21","author":"Davis","year":"2014","journal-title":"Acad. Emerg. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1146\/annurev.physiol.60.1.385","article-title":"PreBotzinger complex and pacemaker neurons: Hypothesized site and kernel for respiratory rhythm generation","volume":"60","author":"Rekling","year":"1998","journal-title":"Annu. Rev. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1113\/jphysiol.2002.031005","article-title":"Modulation of AMPA receptors by cAMP-dependent protein kinase in preB\u00f6tzinger complex inspiratory neurons regulates respiratory rhythm in the rat","volume":"547","author":"Shao","year":"2003","journal-title":"J. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.resp.2010.03.020","article-title":"Role of central neurotransmission and chemoreception on airway control","volume":"173","author":"Kc","year":"2010","journal-title":"Respir. Physiol. Neurobiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2434","DOI":"10.1111\/j.1460-9568.2008.06540.x","article-title":"AMPA and metabotropic glutamate receptors cooperatively generate inspiratory-like depolarization in mouserespiratory neurons in vitro","volume":"28","author":"Pace","year":"2008","journal-title":"Eur. J. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1164\/rccm.200606-778OC","article-title":"Ampakines alleviate respiratory depression in rats","volume":"174","author":"Ren","year":"2006","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1097\/ALN.0b013e31819faa2a","article-title":"Ampakine CX717 protects against fentanyl-induced respiratory depression and lethal apnea in rats","volume":"110","author":"Ren","year":"2009","journal-title":"Anesthesiology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.resp.2009.02.011","article-title":"Ampakine therapy to counter fentanyl-induced respiratory depression","volume":"168","author":"Greer","year":"2009","journal-title":"Respir. Physiol. Neurobiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/clpt.2009.194","article-title":"Selective antagonism of opioid-induced ventilatory depression by an ampakine molecule in humans without loss of opioid analgesia","volume":"87","author":"Oertel","year":"2010","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1152\/japplphysiol.00752.2012","article-title":"Respiratory depression in rats induced by alcohol and barbiturate and rescue by ampakine CX717","volume":"113","author":"Ren","year":"2012","journal-title":"J. Appl. Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1097\/ALN.0b013e318291079c","article-title":"Coadministration of the AMPAKINE CX717 with propofol reduces respiratory depression and fatal apneas","volume":"118","author":"Ren","year":"2013","journal-title":"Anesthesiology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1165\/rcmb.2014-0374OC","article-title":"Stimulation of Respiratory Motor Output and Ventilation in a Murine Model of Pompe Disease by Ampakines","volume":"53","author":"ElMallah","year":"2015","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1164\/rccm.201410-1898OC","article-title":"Ampakines enhance weak endogenous respiratory drive and alleviate apnea in perinatal rats","volume":"191","author":"Ren","year":"2015","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.coph.2014.11.002","article-title":"AMPA receptor potentiators: From drug design to cognitive enhancement","volume":"20","author":"Partin","year":"2015","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_20","unstructured":"Lippa Arnold, S. (2014, January 8\u201311). \u201cStrategic Initiatives in Respiratory Disorders and Key Objectives\u201d. Proceedings of the Rodman and Renshaw 16th Annual Global Investment Conference, New York, NY, USA."},{"key":"ref_21","unstructured":"Street, L., Mueller, R., and Lee, S. (2008). Bicyclic Amide Derivatives for the Treatment of Respiratory Depression. (2008143963), International Patent."},{"key":"ref_22","unstructured":"Mueller, R., and Street, L. (2012). Bicyclic Amides for Enhancing Glutamatergic Synaptic Responses. (8263591), U.S. Patent."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/0378-5173(94)00271-6","article-title":"Drug delivery to the brain. DOPA prodrugs based on a ring-closure reaction to quaternary thiazolium compounds","volume":"116","author":"Toyoaki","year":"1995","journal-title":"Int. J. Pharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3651","DOI":"10.1016\/j.ejmech.2011.05.029","article-title":"Design, synthesis and biological evaluation of brain-specific glucosyl thiamine disulfide prodrugs of naproxen","volume":"46","author":"Fanm","year":"2011","journal-title":"Eur. J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.ejmech.2014.05.072","article-title":"Design, synthesis and biological evaluation of brain targeting L-ascorbic acid prodrugs of ibuprofen with \u201clock-in\u201d function","volume":"82","author":"Zhao","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_26","unstructured":"Quan, W. (2011). Investigation on Receptor Mechanisms Underlying Powerful Antinociception and Low Addiction of Novel. [Ph.D. thesis, Academy of Military Medical Sciences]. Available online: http:\/\/www.cnki.net\/."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/21\/4\/488\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:22:15Z","timestamp":1760210535000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/21\/4\/488"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4,14]]},"references-count":26,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2016,4]]}},"alternative-id":["molecules21040488"],"URL":"https:\/\/doi.org\/10.3390\/molecules21040488","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2016,4,14]]}}}