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Molecules 2016, 21(10), 1332; doi:10.3390/molecules21101332

Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade

1
Centro de Investigación en Biología de la Reproducción, Área Académica de Medicina del Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Pachuca 42090, Hidalgo, México
2
Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, Apdo. Postal 14-740, México City 07360, México
3
Hospital General de los SSH, Pachuca 42070, Hidalgo, México
*
Author to whom correspondence should be addressed.
Received: 5 August 2016 / Revised: 21 September 2016 / Accepted: 30 September 2016 / Published: 7 October 2016
(This article belongs to the Section Medicinal Chemistry)
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Abstract

Uterine relaxation is crucial during preterm labor. Phosphodiesterase-4 (PDE-4) inhibitors have been proposed as tocolytics. Some thalidomide analogs are PDE-4 inhibitors. The aim of this study was to assess the uterus-relaxant properties of two thalidomide analogs, methyl
3-(4-nitrophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl
3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe) and were compared to rolipram in functional studies of spontaneous phasic, K+-induced tonic, and Ca2+-induced contractions in isolated pregnant human myometrial tissues. The accumulation of cAMP was quantified in HeLa cells. The presence of PDE-4B2 and phosphorylated myosin light-chain (pMLC), in addition to the effect of thalidomide analogs on oxytocin-induced pMLC, were assessed in human uterine myometrial cells (UtSMCs). Thalidomide analogs had concentration-dependent inhibitory effects on spontaneous and tonic contractions and inhibited Ca2+-induced responses. Tonic contraction was equipotently inhibited by 4APDPMe and rolipram (IC50 = 125 ± 13.72 and 98.45 ± 8.86 µM, respectively). Rolipram and the thalidomide analogs inhibited spontaneous and tonic contractions equieffectively. Both analogs increased cAMP accumulation in a concentration-dependent manner (p < 0.05) and induced changes in the subcellular localization of oxytocin-induced pMLC in UtSMCs. The inhibitory effects of thalidomide analogs on the contractions of pregnant human myometrium tissue may be due to their PDE-4 inhibitory effect and novel mechanism as calcium-channel blockers. View Full-Text
Keywords: calcium blockers; cAMP; human myometrium; phosphodiesterase-4; preterm labor; relaxation; tocolytics; thalidomide analogs calcium blockers; cAMP; human myometrium; phosphodiesterase-4; preterm labor; relaxation; tocolytics; thalidomide analogs
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Fernández-Martínez, E.; Ponce-Monter, H.; Soria-Jasso, L.E.; Ortiz, M.I.; Arias-Montaño, J.-A.; Barragán-Ramírez, G.; Mayén-García, C. Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade. Molecules 2016, 21, 1332.

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