RESUMO
The prostaglandin-F2α (PGF2α) receptor (FP) was targeted to develop tocolytic agents for inhibiting preterm labor. Azabicycloalkane and azapeptide mimics 2-10 were synthesized based on the (3S,6S,9S)-indolizidin-2-one amino acid analogue PDC113.824 (1), which was shown to modulate FP by a biased allosteric mechanism, involving both Gαq- and Gα12-mediated signaling pathways, and exhibited significant tocolytic activity delaying preterm labor in a mouse model ( Goupil ; et al. J. Biol. Chem. 2010 , 285 , 25624 - 25636 ). Although changes in azabicycloalkane stereochemistry and ring size caused loss of activity, replacement of the indolizidin-2-one amino acid with azaGly-Pro and azaPhe-Pro gave azapeptides 6 and 8, which reduced PGF2α-induced myometrial contractions, potentiated the effect of PGF2α on Gαq-mediated ERK1/2 activation, and inhibited FP modulation of cell ruffling, a response dependent on the Gα12/RhoA/ROCK signaling pathway. Revealing complementarities of azabicycloalkane and azapeptide mimics, novel probes, and efficient tocolytic agents were made to study allosteric modulation of the FP receptor.
Assuntos
Compostos Aza/farmacologia , Trabalho de Parto Prematuro/prevenção & controle , Fragmentos de Peptídeos/farmacologia , Receptores de Prostaglandina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tocolíticos/farmacologia , Contração Uterina/efeitos dos fármacos , Animais , Compostos Aza/síntese química , Compostos Aza/química , Western Blotting , Células Cultivadas , Dinoprosta/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Recém-Nascido , Rim/citologia , Rim/efeitos dos fármacos , Rim/metabolismo , Camundongos , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/química , Gravidez , Prenhez/efeitos dos fármacos , Tocolíticos/síntese química , Tocolíticos/química , Quinases Associadas a rho/metabolismoRESUMO
The influence of stereochemistry and alkyl side chain length on the bioactivity of the Rho kinase inhibitor Y-27632 [(+)-1, R=Me] was examined by the synthesis of (+)- and (-)-1, and two alkyl chain analogs (+)- and (-)-2 (R=n-propyl) and (-)-3 (R=n-octyl) as well as their evaluation in enzymatic and neurite outgrowth assays.