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Chemical modification-mediated optimisation of bronchodilatory activity of mepenzolate, a muscarinic receptor antagonist with anti-inflammatory activity
- Source :
- Bioorganicmedicinal chemistry. 27(15)
- Publication Year :
- 2019
-
Abstract
- The treatment for patients with chronic obstructive pulmonary disease (COPD) usually involves a combination of anti-inflammatory and bronchodilatory drugs. We recently found that mepenzolate bromide (1) and its derivative, 3-(2-hydroxy-2, 2-diphenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (5), have both anti-inflammatory and bronchodilatory activities. We chemically modified 5 with a view to obtain derivatives with both anti-inflammatory and longer-lasting bronchodilatory activities. Among the synthesized compounds, (R)-(-)-12 ((R)-3-(2-hydroxy-2,2-diphenylacetoxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane bromide) showed the highest affinity in vitro for the human muscarinic M3 receptor (hM3R). Compared to 1 and 5, (R)-(-)-12 exhibited longer-lasting bronchodilatory activity and equivalent anti-inflammatory effect in mice. The long-term intratracheal administration of (R)-(-)-12 suppressed porcine pancreatic elastase-induced pulmonary emphysema in mice, whereas the same procedure with a long-acting muscarinic antagonist used clinically (tiotropium bromide) did not. These results suggest that (R)-(-)-12 might be therapeutically beneficial for use with COPD patients given the improved effects seen against both inflammatory pulmonary emphysema and airflow limitation in this animal model.
- Subjects :
- medicine.drug_class
Swine
Clinical Biochemistry
Pharmaceutical Science
Pharmacology
Benzilates
01 natural sciences
Biochemistry
Anti-inflammatory
chemistry.chemical_compound
Mice
Structure-Activity Relationship
Piperidines
Bromide
Drug Discovery
Muscarinic acetylcholine receptor
Administration, Inhalation
medicine
Animals
Mepenzolate
Molecular Biology
Receptor, Muscarinic M3
Dose-Response Relationship, Drug
Molecular Structure
Pancreatic Elastase
010405 organic chemistry
Chemistry
Organic Chemistry
Anti-Inflammatory Agents, Non-Steroidal
Antagonist
Muscarinic antagonist
Muscarinic acetylcholine receptor M3
Tiotropium bromide
0104 chemical sciences
Bronchodilator Agents
010404 medicinal & biomolecular chemistry
Pulmonary Emphysema
Molecular Medicine
medicine.drug
Subjects
Details
- ISSN :
- 14643391
- Volume :
- 27
- Issue :
- 15
- Database :
- OpenAIRE
- Journal :
- Bioorganicmedicinal chemistry
- Accession number :
- edsair.doi.dedup.....a709a0bc136e7167ff2157dc84d9dba8