In the course of various studies on the importance of ring size to the biological activity of oxytocin and deamino-oxytocin, we have synthesized the next higher and next lower homologs of deamino-oxytocin. Deamino-oxytocin (1-Beta-mercaptopropionic acid-oxytocin) has almost twice the avian vasodepressor activity and about one and one-half times the oxytocic activity of oxytocin. As in oxytocin the deamino-oxytocin possesses a 20-membered disulfide ring. To study the effect of ring size we therefore synthesized 1-gamma-mercaptobutyric acid) -oxytocin and 1-(mercaptoacetic acid)-oxytocin, the former therefore possessing a 21-membered ring and the latter a 19-membered ring. The gamma- mercaptobutyric acid analog was found to be practically devoid of biological activity and the mercaptoacetic acid analog to have a very slight degree of activity. We now have underway the synthesis of the 19 and 21-membered ring analogs of 1-deamino-lysine-vasopressin by a similar approach. The dramatic effect of the almost complete elimination of oxytocic activity of the highly potent deamino-ozytocin by increasing the size of the ring from 20 to 21 members by the formal insertion of a "CH2" group at position 1 of deamino-oxytocin has aroused our interest in extending the work to the synthesis and pharmacological study of other 21-membered ring analogs. The question arises as to whether the formal insertion of a "CH2" group at some other position in the ring would affect the oxytocic activity of deamino-oxytocin as it did at the 1 position. This particular aspect of these studies can be approached by substituting a Beta-homo-amino acid in place of an alpha-amino acid present in oxytocin and deamino-oxytocin. By doing this the ring is enlarged but the side chain attached to the backbone structure remains the same. This work is still underway.
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