Synthesis and contractile activity of new pseudopeptido and thioaromatic analogues of leukotriene D4.
Seven new pseudopeptido and thioaromatic leukotriene analogues were synthesized and their agonist-antagonist and binding activities investigated. The synthesis led to the pleasing observation that the analogue in which the cysteinyl-glycine moiety was replaced by a 6-mercapto-3-(E)-hexenoic acid, not only exhibited potent affinity (guinea-pig lung parenchyma, IC50: 5 x 10(-9) M) but also showed 30% of the LTD4 agonist activity (guinea-pig ileum, ED 50: 2.7 x 10(-9)) giving very important key information on LTD4 geometry to the receptor. This compound was the first stable new pseudopeptido-leukotriene with such agonist activity and should contribute to the understanding of the metabolism of leukotriene D4. In addition, inversion of chirality at C5 and C6 carbon atoms of the leukotriene chain or replacement of the cysteinyl-glycine moiety by a thioaromatic acid led to new weak antagonists of the LTD4.
Niel
N
N
Laboratoire de Chimie des Mediateurs et Physicochimie des Interactions Biologiques associe au C.N.R.S., Faculte de Pharmacie, Universite Montpellier I, France.
Rechencq
E
E
Muller
A
A
Vidal
J P
JP
Escale
R
R
Durand
T
T
Girard
J P
JP
Rossi
J C
JC
Bonne
C
C
D000818:Animals; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D011971:Receptors, Immunologic / Q000187:drug effects; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A