NK拮抗薬, FK224およびFK888の創出とその薬理作用
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概要
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In order to create a new drug for the treatment of respiratory diseases, such as asthma and chronic bronchitis, having a novel therapeutic mechanism, we have been trying to develop new compounds with neurokinin (NK)-receptor antagonistic effects. We used [<SUP>3</SUP>H]-substance P binding to guinea pig lung membrane for the first screening system and successfully discovered FK224 from a fermentation product and FK888 from chemical design studies using an octapeptide antagonist (D-Pro<SUP>4</SUP>, D-Trp<SUP>7, 9, 10</SUP>) SP<SUB>4-11</SUB> as the parent compound. FK224 and FK888 showed different selectivities against the NK-receptor subtypes (NK<SUB>1</SUB>, NK<SUB>2</SUB>, NK<SUB>3</SUB>); FK888 was a highly potent NK<SUB>1</SUB>-selective antagonist, and FK224 was a NK<SUB>1</SUB> +NK<SUB>2</SUB> dual receptor antagonist. Neither compound had any activity on the NK<SUB>3</SUB> receptor. In the in vivo experiments, FK224 and FK888 significantly inhibited the constriction and plasma extravasation in the airway induced by agonist injection. These compounds also showed inhibitory effects on the airway response induced by capsaicin and antidromic stimulation of vagus nerves. Furthermore, FK224 and FK888 were effective on the mucus secretion in the airway and the cough reflex induced by citric acid challenge. There were some differences in the effects of FK224 and FK888 in the in vivo experiments, and it was suggested that the NK<SUB>1</SUB> receptor and NK<SUB>2</SUB> receptor were mainly involved in neurogenic inflammation and airway constriction, respectively. FK224 and FK888 are now undergoing clinical studies to test the effectiveness of a NK antagonist in human respiratory diseases.
- 社団法人 日本薬理学会の論文
- 1995-09-01
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