2024-03-29T00:29:23Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/608562020-07-22T09:23:50Zcom_10261_86com_10261_1col_10261_339
2012-11-22T09:59:59Z
urn:hdl:10261/60856
Structure-activity relationship study of opiorphin, a human dual ectopeptidase inhibitor with antinociceptive properties
Rosa, Mónica
Arsequell, Gemma
Rougeot, Catherine
Calle Jiménez, Luis Pablo
Marcelo, Filipa
Pinto, Marta
Centeno, Nuria B.
Jiménez-Barbero, Jesús
Valencia Parera, Gregorio
8 páginas, 4 figuras, 3 tablas, 1 esquema -- PAGS nros. 1181-1188
Toward developing new potential analgesics, this first structure–activity relationship study of opiorphin (H-Gln-Arg-Phe-Ser-Arg-OH), a human peptide inhibiting enkephalin degradation, was performed. A systematic Ala scanning proved that Phe3 is a key residue for neprilysin and aminopeptidase N (AP-N) ectoenkephalinase inhibition. A series of Phe3-halogenated analogues revealed that halogen bonding based optimization strategies are not applicable to this residue. Additional substituted Phe3 derivatives showed that replacing l-Phe3 for d-Phe3 increased the AP-N inhibition potency by 1 order of magnitude. NMR studies and molecular mechanics calculations indicated that the improved potency may be due to CH−π stacking interactions between the aromatic ring of d-Phe3 and the Hγ protons of Arg2. This structural motif is not possible for the native opiorphin and may be useful for the design of further potent and metabolically stable analogues
2012-11-22T09:59:59Z
2012-11-22T09:59:59Z
2012-02-09
artículo
Journal of Medicinal Chemistry 55(3):1181-1188 (2012)
0022-2623
http://hdl.handle.net/10261/60856
10.1021/jm2012112
1520-4804
eng
http://dx.doi.org/10.1021/jm2012112
closedAccess
American Chemical Society