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Title

Amino acid and peptide prodrugs of diphenylpropanones positive allosteric modulators of α7 nicotinic receptors with analgesic activity

AuthorsBalsera, Beatriz; Mulet, José; Sala, Salvador; Sala, Francisco; Torre-Martínez, Roberto de la; González-Rodríguez, Sara; Plata, A.; Naesens, L.; Fernández-Carvajal, Asia; Ferrer-Montiel, Antonio; Criado, Manuel ; Pérez de Vega, M. Jesús; González-Muñiz, Rosario
KeywordsAllosteric modulation
a7 nicotinic receptors
Diphenylpropanones
DDP-IV
Diketopiperazines
Prodrugs
Issue Date2018
PublisherElsevier
CitationEuropean Journal of Medicinal Chemistry 143: 157-165 (2018)
Abstractα7 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 α7 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 antinociceptive 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.
Publisher version (URL)http://dx.doi.org/10.1016/j.ejmech.2017.10.083
URIhttp://hdl.handle.net/10261/172095
Identifiersdoi: 10.1016/j.ejmech.2017.10.083
issn: 0223-5234
e-issn: 1768-3254
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