Functional relaxant effect of 6,7-dipropoxy-2H-chromen-2-one is mainly by calcium channel blockade in ex vivo assay of tracheal rings

• Published in: Medicinal chemistry research 2019-08, Vol.28 (8), p.1197-1204
• Main Authors: Sánchez-Recillas, Amanda, Estrada-Soto, Samuel, Navarrete-Vázquez, Gabriel, Millán-Pacheco, César, Ortiz-Andrade, Rolffy, Villalobos-Molina, Rafael, Ibarra-Barajas, Maximiliano, Gallardo-Ortiz, Itzell A.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Acetylcholine receptors (muscarinic); ASTHMA; Biochemistry; BIOLOGICAL EFFECTS; Biomedical and Life Sciences; Biomedicine; CALCIUM; Calcium channels (L-type); Calcium chloride; CALCIUM CHLORIDES; Calcium influx; Carbachol; Cell Biology; Chronic obstructive pulmonary disease; Contraction; COUMARIN; EDEMA; INFLAMMATION; Lung diseases; Mucus; Muscles; Nifedipine; Obstructive lung disease; Original Research; p53 Protein; Pharmacology; Pharmacology/Toxicology; Potassium chloride; POTASSIUM CHLORIDES; RATS; RECEPTORS; Respiratory tract; Respiratory tract diseases; Rodents; Smooth muscle; THEOPHYLLINE
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-019-02364-y

Asthma is a prevalent disease characterized by airway chronic inflammation, airway hyperresponsiveness, edema and excess of mucus production. Molecules with coumarin scaffold have shown multiple biological effects, including anti-asthmatic. This study describes relaxant effect and mechanism of action of novel semisynthetic 6,7-dipropoxy-2 H -chromen-2-one ( 6,7-DPC ) on smooth muscle airways and in silico approaches. 6,7-DPC induced significant relaxant effect on tracheal rings pre-contracted with carbachol (E max  = 100%; EC 50  = 89 µM). Concentration-response curve of 6,7-DPC showed a significant shift to the left with respect to theophylline (positive control). Moreover, pre-treatment with 6,7-DPC inhibited the carbachol-induced contraction in a concentration-dependent manner with suppression of the maximum response. Also, KCl [80 mM]-induced contraction was partially abolished by 6,7-DPC compared with nifedipine; however, CaCl 2 contraction curve only reached 30% of maximal response in the tissues pre-incubated with the test sample. 6,7-DPC was docked on an outer cavity located on the intracellular side of the human L-type calcium channel model and interacts in the following chains and residues: IIIS5.M26, IIIP.T45, IIIP.F49, IIIP.G51, IIIP.P53, IVP.C46, IVP.G49, IVP.E50, IVP.A51, IVP.W52, IVP.Q53, IVP.D54, IVS6.I4, IVS6.F7, IVS6.I8, IVS6.F10, and IVS6.F11. Also, nifedipine made unique interactions with IIIP.E50, IIIP.W52, IIIP.L55. Meanwhile, 6,7-DPC interacted with IIIS5.A22, IIIS2.Q27, and IVS6.C14, exclusively. In conclusion, 6,7-DPC showed a relaxant effect due to combined mechanism of action on rat tracheal rings, through non-competitive muscarinic receptor functional antagonism and preventing the calcium influx. This provides pharmacological basis for the use of 6,7-DPC in airways disorders, such as asthma or chronic obstructive pulmonary disease (COPD).