Synthesis of three oxytocin analogs related to [1-deaminopenicillamine]oxytocin prossessing antioxytocic activity

Abstract

ß-ß ß -ß,ß-ß : acidjoxytocin, analogs of deaminopenicillamine-oxytocin, have been synthesized from a common protected octapeptide resin intermediate and purified by sequential gel filtration on Sephadex G-15 in 50% AcOH and 0.2 N AcOH. The 3 compounds were devoid of oxytocic and avian vasodepressor activities, but all showed a significant degree of inhibition of the effects of oxytocin on the isolated rat uterus and on avian blood pressure. Each compound showed approximately the same inhibitory potency in both biological systems when compared to that of deaminopenicillamineoxytocin. [1-Mercaptodimethylacetic acidjoxytocin and [ 1 -ß-mercapto-a,a-dimethylpropionic acidjoxytocin had about 20% and 33 to 47%, respectively, of the inhibitory potency of deaminopenicillamineoxytocin. [ 1 -ß-Mercapto-ß,ß-diethylpropionic acidjoxytocin had approximately twice the inhibitory potency of deaminopenicillamine-oxytocin ([ 1 ^-mercapto^^-dimethylpropionic acidjoxytocin in both systems.

Relative conformational rigidity in oxytocin and (1-penicillamine)-oxytocin: a proposal for the relationship of conformational flexibility to peptide hormone agonism and antagonism.

“…In Table 3 (31)(32)(33)(34)(35)(36)(37)(38). We further predict that for small peptide hormones, an analog designed to reduce the flexibility of the hormone has a high probability of either reduced agonist bio- (34).…”

Uterine Receptors for Oxytocin: Correlation Between Antagonist Potency and Receptor Binding

“…In addition to being an oxytocin antagonist, [Nacetyl, 2-0-methyl-tyrosine]oxytocin is a partial agonist (Krejci, Kupkova, Barth & Jost, 1973). The diethyl-and pentamethylene-propionic acid antagonists, however, appear to be devoid of oxytocic activity (Vavrek, Ferger, Allen, Rich, Blomquist & Du Vigneaud, 1972;Nestor, Ferger & Du Vigneaud, 1975). Partial agonists/competitive antagonists are postulated to be capable of full receptor occupancy, but they either dissociate very slowly from the receptor (Paton, 1961) or they lack some of the structural characteristics necessary for the initiation of the stimulus (Ariens et al, 1956;Stephenson, 1956).…”

[1-.beta.-Mercapto-.beta.,.beta.-diethylpropionic acid]-8-lysine-vasopressin, a potent inhibitor of 8-lysine-vasopressin and of oxytocin

“…(2). After drying (MgSOd), filtration, and concentration of the solution, the resultant straw-colored oil crystallized as long needles.…”