Abstract
In the field of experimental pharmacology, researchers continuously investigate new relaxant agents of the airway smooth muscle cells (ASMCs), since the pathophysiology of respiratory illnesses, such as asthma, involves hyperresponsiveness and changes in ASMC homeostasis. In this scenario, labdane-type diterpenes, like forskolin (FSK), are a class of compounds known for their relaxing action on smooth muscle cells (SMCs), being this phenomenon related to the direct activation of AC-cAMP-PKA pathway. Considering the continuous effort of our group to study the mechanism of action and prospecting for compounds isolated from natural sources, in this paper, we presented how the diterpene 8(17),12E,14-labdatrien-18-oic acid (LBD) promotes relaxant effect on ASMC, performing in vitro experiments using isolated guinea pig trachea and in silico molecular docking/dynamics simulations. In vitro experiments showed that in the presence of aminophylline, FSK and LBD had their relaxant effect potentiated (EC50 from 1.4 ± 0.2 × 10−5 M to 1.5 ± 0.3 × 10−6 M for LBD and from 2.0 ± 0.2 × 10−7 M to 6.4 ± 0.4 × 10−8 M for FSK) while in the presence of Rp-cAMPS this effect was attenuated (EC50 from 1.4 ± 0.2 × 10−5 M to 3 × 10−4 M for LBD and from 2.0 ± 0.2 × 10−7 to 3.1 ± 1.0 × 10−6 M for FSK). Additionally, in silico simulations evidenced that the lipophilic character of LBD is probably responsible for its stability on AC binding site. LBD presented two preferential orientations, where the double bonds of the isoprene moiety as well as the unique polar group (carboxylic acid) in this compound form important anchoring points. In this sense, we consider that the LBD can interact stabilizing the catalytic dimmer of AC as the FSK, although less efficiently.
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Acknowledgments
The authors thank the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior–Brazil (CAPES)–Finance code 001, which partially financed this study. Molecular graphics images were produced using the UCSF Chimera package from the Computer Graphics Laboratory, University of California, San Francisco (supported by NIH P41 RR-01081). The authors acknowledge the Universidade Federal do Vale do São Francisco (UNIVASF), Centro Nacional de Processamento de Alto Desempenho da Universidade Federal do Ceará (CENAPAD-UFC), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).
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EBAF and LAAR conceived and designed the research. EBAF, LAAR, and TGCC conducted the experiments. JFT, MSS, and BAS contributed new reagents or analytical tools. EBAF, LAAR, FSS, LAMSDF, EGB, and PMNM analyzed the data. EBAF, LAAR, LAMSDF, and PMNM wrote the manuscript. All authors read and approved the manuscript and all data generation was in-house so that there was no use of paper sheets.
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Highlights
• A labdane-type diterpene 8(17),12E,14-labdatrien-18-oic acid (LBD) relaxes rat trachea smooth muscle by direct activation of AC-cAMP-PKA pathway.
• Relaxant effect of LBD is attenuated by Rp-cAMS and potentiated by aminophylline.
• Molecular dynamic simulations showed that the tested compound (LBD) complexes are less stable than the standard drug Forskolin, corroborating the experimental data and relative potency.
• The lipophilic character of LBD together with one possible hydrogen bond and one pi-pi anchoring can explain the interaction and stabilization of the C1/C2 catalytic domains of the adenylyl cyclase enzyme, although less efficiently than FSK.
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Alencar Filho, E.B., Ribeiro, L.A.A., Carvalho, T.G.C. et al. In vitro and in silico studies of 8(17),12E,14-labdatrien-18-oic acid in airways smooth muscle relaxation: new molecular insights about its mechanism of action. Naunyn-Schmiedeberg's Arch Pharmacol 394, 885–902 (2021). https://doi.org/10.1007/s00210-020-02010-0
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DOI: https://doi.org/10.1007/s00210-020-02010-0