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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.
Alencar Filho, Edilson B; Ribeiro, Luciano A A; Carvalho, Thiego G C; Silva, Fabrício S; Duarte-Filho, Luiz Antonio M S; Barbosa, Euzébio G; Menezes, Pedro M N; Tavares, Josean F; da Silva, Marcelo S; Silva, Bagnólia A.
Afiliación
  • Alencar Filho EB; Collegiate of Pharmaceutical Sciences, Postgraduate Program in Biosciences (ex-Natural Resources of Semi-arid), Postgraduate Program in Health and Biological Sciences, Federal University of San Francisco Valley (UNIVASF), Petrolina, Pernambuco, Brazil. edilson.beserra@univasf.edu.br.
  • Ribeiro LAA; Collegiate of Pharmaceutical Sciences, Postgraduate Program in Biosciences (ex-Natural Resources of Semi-arid), Federal University of San Francisco Valley (UNIVASF), Petrolina, Pernambuco, Brazil. luciano.ribeiro@univasf.edu.br.
  • Carvalho TGC; Collegiate of Pharmaceutical Sciences, Postgraduate Program in Biosciences (ex-Natural Resources of Semi-arid), Postgraduate Program in Health and Biological Sciences, Federal University of San Francisco Valley (UNIVASF), Petrolina, Pernambuco, Brazil.
  • Silva FS; Collegiate of Pharmaceutical Sciences, Postgraduate Program in Biosciences (ex-Natural Resources of Semi-arid), Federal University of San Francisco Valley (UNIVASF), Petrolina, Pernambuco, Brazil.
  • Duarte-Filho LAMS; Collegiate of Pharmaceutical Sciences, Postgraduate Program in Biosciences (ex-Natural Resources of Semi-arid), Federal University of San Francisco Valley (UNIVASF), Petrolina, Pernambuco, Brazil.
  • Barbosa EG; Collegiate of Pharmacy, Chemistry Laboratory, Lagoa Nova University Campus, Federal University of Rio Grande do Norte (UFRN), PO Box 1524, Natal, RN, CEP 59078-970, Brazil.
  • Menezes PMN; Northeast Biotechnology Network (RENORBIO), Federal Rural University of Pernambuco (UFRPE), Rua Dom R. Manuel de Medeiros, s / n, Dois Irmãos, Recife, PE, CEP 52171-900, Brazil.
  • Tavares JF; Pharmaceutical Technology Laboratory (LTF), Federal University of Paraíba (UFPB), Cidade Universitária, Castelo Branco, PO Box 5009, João Pessoa, PB, 58051-970, Brazil.
  • da Silva MS; Pharmaceutical Technology Laboratory (LTF), Federal University of Paraíba (UFPB), Cidade Universitária, Castelo Branco, PO Box 5009, João Pessoa, PB, 58051-970, Brazil.
  • Silva BA; Pharmaceutical Technology Laboratory (LTF), Federal University of Paraíba (UFPB), Cidade Universitária, Castelo Branco, PO Box 5009, João Pessoa, PB, 58051-970, Brazil.
Naunyn Schmiedebergs Arch Pharmacol ; 394(5): 885-902, 2021 05.
Article en En | MEDLINE | ID: mdl-33205250
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tráquea / Miocitos del Músculo Liso / Diterpenos / Relajación Muscular Límite: Animals Idioma: En Revista: Naunyn Schmiedebergs Arch Pharmacol Año: 2021 Tipo del documento: Article País de afiliación: Brasil Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tráquea / Miocitos del Músculo Liso / Diterpenos / Relajación Muscular Límite: Animals Idioma: En Revista: Naunyn Schmiedebergs Arch Pharmacol Año: 2021 Tipo del documento: Article País de afiliación: Brasil Pais de publicación: Alemania