Synthesis of Oxytocin Analogues with Replacement of Sulfur by
Carbon Gives Potent Antagonists with Increased Stability
Jake L. Stymiest,Bryan F. Mitchell,Susan Wong, andJohn C. Vederas*
Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2, and Perinatal
Research Centre, Department of Obstetrics and Gynecology, University of Alberta, Canada TH5 3V9
john.vederas@ualberta.ca
Received March 16, 2005
Abstract:
The neuropeptide oxytocin 1 controls mammary and uterine smooth muscle contraction. Atosiban
2, an oxytocin antagonist, is used for prevention of preterm labor and premature birth. However,
the metabolic lifetimes of such peptide drugs are short because of in vivo degradation. Facile
production of oxytocin analogues with varying ring sizes wherein sulfur is replaced by carbon
(methylene or methine) could be achieved by standard solid-phase peptide synthesis using olefin-bearing amino acids followed by on-resin ring-closing metathesis (RCM). These were tested for
agonistic and antagonistic uteronic activity using myometrial strips taken from nonpregnant female
rats. Peptide 8 showed agonistic activity in vitro (EC50 = 1.4 × 103 ± 4.4 × 102 nM) as compared
to 1 (EC50 = 7.0 ± 2.1 nM). Atosiban analogues 17 (pA2 = 7.8 ± 0.1) and 18 (pA2 = 8.0 ± 0.1)
showed substantial activity compared to the parent oxytocin antagonist 2 (pA2 = 9.9 ± 0.3). Carba
analogue 35 (pA2 = 6.1 ± 0.1) had an agonistic activity over 2 orders of magnitude less than its
parent 3 (8.8 ± 0.5). A comparison of biological stabilities of 1,6-carba analogues of both an agonist
8 and antagonist 18 versus parent peptides 1 and 2 was conducted. The half-lives of peptides 8
and 18 in rat placental tissue were shown (Table 2) to be greatly improved versus their parents
oxytocin 1 and atosiban 2, respectively. These results suggest that peptides 8 and 18 and analogues
thereof may be important leads into the development of a long-lasting, commercially available
therapeutic for initiation of parturition and treatment of preterm labor.
