2024-03-28T08:12:37Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1720952023-01-10T13:44:05Zcom_10261_103com_10261_1com_10261_81com_10261_5com_10261_133col_10261_356col_10261_334col_10261_386
Amino acid and peptide prodrugs of diphenylpropanones positive allosteric modulators of α7 nicotinic receptors with analgesic activity
Balsera, Beatriz
Mulet Soler, 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
Ministerio de Economía, Industria y Competitividad (España)
Generalitat Valenciana
European Commission
Allosteric modulation
a7 nicotinic receptors
Diphenylpropanones
DDP-IV
Diketopiperazines
Prodrugs
α7 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.
Funding: This work was supported by the Spanish Ministerio de
Economía y Competitividad (MINECO) SAF2011-22802, BFU2015-
70067-REDC and SAF2015-66275-C2-R, and the Generalitat
Valenciana, PROMETEO/2014/011. BBP thanks the CSIC for a predoctoral
fellowship (JAE-Predoc from Junta para la Ampliación de
Estudios, co-financed by FSE).
Peer Reviewed
2018-11-12T11:06:06Z
2018-11-12T11:06:06Z
2018
2018-11-12T11:06:06Z
artículo
http://purl.org/coar/resource_type/c_6501
doi: 10.1016/j.ejmech.2017.10.083
issn: 0223-5234
e-issn: 1768-3254
European Journal of Medicinal Chemistry 143: 157-165 (2018)
http://hdl.handle.net/10261/172095
10.1016/j.ejmech.2017.10.083
http://dx.doi.org/10.13039/501100000780
http://dx.doi.org/10.13039/501100003359
http://dx.doi.org/10.13039/501100010198
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2015-70067-REDC
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-66275-C2-R
http://dx.doi.org/10.1016/j.ejmech.2017.10.083
Sí
none
Elsevier