Synthesis and LTD4 antagonist activity of 2-norleukotriene analogs

A series of structural analogues of 4(R)-hydroxy-5(S)-cysteinylglycyl-6(Z)-nonadecenoic acid [4R,5S,6Z)-2-nor-LTD1 (10b), SK&F 101132) has been synthesized and pharmacologically characterized. (4R,5S,6Z)-2-nor-LTD1 significantly antagonized LTD4-induced contractile responses on isolated guinea p...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1985-12, Vol.28 (12), p.1847-1853
Main Authors: Ku, Thomas W, McCarthy, Mary E, Weichman, Barry M, Gleason, John G
Format: Article
Language:English
Subjects:
Animals
Chemical Phenomena
Chemistry
Exact sciences and technology
Guinea Pigs
Male
Muscle Contraction - drug effects
Organic chemistry
Peptides
Preparations and properties
SRS-A - analogs & derivatives
SRS-A - antagonists & inhibitors
SRS-A - chemical synthesis
SRS-A - pharmacology
Structure-Activity Relationship
Trachea - physiology
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Summary:A series of structural analogues of 4(R)-hydroxy-5(S)-cysteinylglycyl-6(Z)-nonadecenoic acid [4R,5S,6Z)-2-nor-LTD1 (10b), SK&F 101132) has been synthesized and pharmacologically characterized. (4R,5S,6Z)-2-nor-LTD1 significantly antagonized LTD4-induced contractile responses on isolated guinea pig trachea. The cis double-bond geometry appears to be critical for antagonist activity, whereas the trans isomer 17 exhibited weak contractile activity. Replacement of the cysteinylglycyl moiety with cysteine afforded 20, which retained significant antagonist activity, while lengthening or shortening the lipid tail by five methylene groups resulted in complete loss of activity. The eicosanoid amide 15, glycinamide 14, and C-1 carbinol 18 analogues all possessed antagonist activity, whereas the diol derivative 19 exhibited increased intrinsic agonist activity.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00150a016