Two highly effective V1/V2 antagonists of vasopressin containing novel thioacids at position 1.
In an attempt to develop more effective and selective V1/V2 antagonists of arginine vasopressin (AVP), two analogues have been designed and synthesized. In position 1 they contain thioacids that include a heteroatom in the cyclohexane ring. The 4-thio-4-tetrahydrothiopyraneacetic acid modification of position 1 used in one of them had advantages over the 1-mercaptocyclohexaneacetic acid substituted compound used as reference. The new compound was weaker at lower doses, but elicited a greater response at higher doses, whereas the reference compound reached its plateau earlier. Although the 4-thio-4-tetrahydropyraneacetic acid substitution used in the second compound resulted in a less potent analogue on a weight basis, this substitution also confers enhanced overall efficacy in terms of magnitude of effect.
Department of Medicine, Boston University Medical Centre, MA 02118.
B
B
Lammek
Y X
YX
Wang
R
R
Franco
I
I
Gavras
H
H
Gavras
D000818:Animals; D001127:Arginine Vasopressin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D001127:Arginine Vasopressin; C069496:argipressin, 1-(4-thio-4-tetrahydropyranoacetic acid)-O-Et-Tyr(2)-Val(4)-; C069497:argipressin, 1-(4-thio-4-tetrahydrothiopyranoacetic acid)-O-Et-Tyr(2)-Val(4)-