Amino acid and peptide prodrugs of diphenylpropanones positive allosteric modulators of alpha 7 nicotinic receptors with analgesic activity

alpha 7 Nicotinic acetylcholine receptors (nAChRs) are ion channels implicated in a number of CNS pathological processes, including pain and psychiatric, cognitive and inflammatory diseases. Comparing with orthosteric agonism, positive allosteric modulation of these channels constitutes an interesti...

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Published inEuropean journal of medicinal chemistry Vol. 143; pp. 157 - 165
Main Authors Balsera, Beatriz, Mulet, Jose, Sala, Salvador, Sala, Francisco, de la Torre-Martinez, Roberto, Gonzalez-Rodriguez, Sara, Plata, Adrian, Naesens, Lieve, Fernandez-Carvajal, Asia, Ferrer-Montiel, Antonio, Criado, Manuel, Perez de Vega, Maria Jesus, Gonzalez-Muniz, Rosario
Format Journal Article
LanguageEnglish
Published ISSY-LES-MOULINEAUX Elsevier 01.01.2018
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
NEUROPATHIC PAIN
ACETYLCHOLINE-RECEPTORS
ACYCLOVIR
Prodrugs
NACHR AGONISTS
DDP-IV
alpha 7 nicotinic receptors
Diphenylpropanones
TARGETS
HYPERALGESIA
Allosteric modulation
Diketopiperazines
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Summary:alpha 7 Nicotinic acetylcholine receptors (nAChRs) are ion channels implicated in a number of CNS pathological processes, including pain and psychiatric, cognitive and inflammatory diseases. Comparing with orthosteric agonism, positive allosteric modulation of these channels constitutes an interesting approach to achieve selectivity versus other nicotinic receptors. We have recently described new chalcones and 1,3-diphenylpropanones as positive allosteric modulators (PAMs) of alpha 7 nAChRs, which proved to have good analgesic activities but poor pharmacokinetic properties. Here we report the preparation of amino acid and peptide derivatives as prodrugs of these modulators with the aim of improving their in vivo biological activity. While the valine derivative showed very short half life in aqueous solutions to be considered a prodrug, Val-Val and Val-Pro-Val are suitable precursors of the parent 1,3-diphenylpropanones, via chemical and enzymatic transformation, respectively. Compounds 19 (Val-Val) and 21 (Val-Pro-Val), prodrugs of the 2',5',4-trihydroxy-1,3-diphenylpropan-1-one 3, showed significant antinociceptiye activity in in vivo assays. The best compound, 21, displayed a better profile in the analgesia test than its parent compound 3, exhibiting about the same potency but long-lasting effects. (C) 2017 Elsevier Masson SAS. All rights reserved.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2017.10.083