The Design and Synthesis of Long-Acting Oxytocin Antagonists Substituted in Positions 2, 7, and 8

The design of oxytocin antagonists (for reviews, see Hruby and Mosberg, 1982; Hruby and Smith, 1987; Hruby et al., 1990; Lebl, 1987; Manning and Sawyer, 1989; Sawyer and Manning, 1985) has increasingly involved a search for structural changes that would enhance both in vivo potency and increase duration of action. The discovery of Shulz and du Vigneaud (1966, 1967) and Jost et al. (1961) that substituting more bulky amino acids in either position 1 (penicillamine) or position 2 (O-methyltyrosine) produced oxytocin antagonists has led to numerous further investigations into the structural and conformational requirements important for antagonism at the uterine oxytocin receptor (Hruby, 1985; Hruby et al., 1990; Manning and Sawyer, 1989; Meraldi et al., 1975, 1977). Since these pioneering studies, many important, more potent antagonists have been reported, particularly by the groups of Manning et al., Melin et al., Lebl et al., and Hruby et al. (Hruby and Smith, 1987; Lebl, 1987; Manning and Sawyer, 1985) primarily by incorporating appropriate amino acid substitutions into positions 1, 2, 4, 7, and 8, including linear analogs (Manning et al., 1987).