Syntheses and biological activities of endothelin-1 analogs.
Endothelin-1 analogs replaced by various amino acids at position 21, namely [X21]-ET-1, were synthesized, and their agonistic vasoconstrictor activity on rat thoracic aortic strips and receptor binding activity on rat brain membrane fraction were examined to elucidate their structure-activity relationship. The vasoconstrictor activities of [Tyr21]- and [Phe21]-ET-1 were one order of magnitude smaller than that of ET-1, and those of [His21]-, [Gly21]-, [Ser21]-, [Ala21]- and [Lys21]-ET-1 were more than two orders of magnitude smaller than that of ET-1. On the other hand, the replacements by Ile, Glu, Gln and Pro resulted in distinguished losses of the vasoconstrictor activities. In addition, preincubation with these analogs did not blunt ET-1-induced vasoconstriction and showed no antagonistic activity. The binding inhibitory activities of these analogs against 125I-ET-1 were approximately conformable to the vasoconstrictor activities with only a slight exception. These findings demonstrate that the phenyl group at position 21 is important for both the vasoconstrictor activity and the receptor binding activity.
Koshi
T
T
Tokyo Research Laboratories, Kowa Company, Ltd., Japan.
Suzuki
C
C
Arai
K
K
Mizoguchi
T
T
Torii
T
T
Hirata
M
M
Ohkuchi
M
M
Okabe
T
T
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D016232:Endothelins / Q000138:chemical synthesis* / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism; D017466:Receptors, Endothelin
D016232:Endothelins; D011956:Receptors, Cell Surface; D017466:Receptors, Endothelin