4-Threonine Analogues of Neurohypophysial Hormones With Selectively Enhanced Oxytocin-Like Activities

Abstract

The 4-threonine analogues of oxytocin and of mesotocin and isotocin were prepared by solid-phase synthesis. -oxytocin is about twice as active as oxytocin in rat uterus assays in vitro and in vivo and about three times as active in fowl vasodepressor assays. It is slightly more active than oxytocin in rat or rabbit milk-ejection assays. When infused intravenously into water-loaded rats it causes much less depression of diuresis than does an equal dose of oxytocin. [4-Threonine]-oxytocin has much less vasopressor activity than oxytocin. [4-Threonine]-mesotocin also shows enhanced oxytocin-like properties. Its oxytocic activity is equal to or greater than that of oxytocin and its fowl vasodepressor potency is about the same as that of [4-threonine]-oxytocin, 1500 u./mg. It also has less antidiuretic and vasopressor activities than mesotocin. Thus 4-threonine analogues, containing nothing but common L-amino acids, appear to have more of the specific oxytocin-like properties and less of the vasopressin\x=req-\ like properties than do oxytocin or mesotocin. Thus they may be considered improvements on the natural hormones. In this respect they are unique among the reported synthetic analogues of natural peptide hormones.Substitution of 4-threonine in the weakly-active analogue [3-leucine]\x=req-\ oxytocin also increases its oxytocic and fowl vasodepressor activities. Thus a threonine in the 4-position appears to endow oxytocin-like peptides with greater specific activities than do the amino acids that occur naturally in this position, glutamine and serine. These observations may be of interest when considered (a) from an evolutionary viewpoint, (b) in attempting to interpret relations between molecular structures and biological activities, and (c) as describing peptides with more of the desired properties of oxytocin and less of the undesired properties which might have therapeutic advantages over the natural hormone.

Combined high oxytocic with negligible antidiuretic and pressor activities in multisubstituted oxytocins

“…Similar effects were previously noted for [Thr4]oxytocin. 39 In the rat pressor assay, both 2 and 4 caused a depressor prior to a pressor response (illustrated for 4, Figure 1).…”

Synthesis and some pharmacological properties of [4-threonine,7-glycine]oxytocin, [1-(L-2-hydroxy-3-mercaptopropanoic acid),4-threonine,7-glycine]oxytocin (hydroxy[thr4, gly7]oxytocin), and [7-glycine]oxytocin, peptides with high oxytocic-antidiuretic selectivity

“…A number of 4-substituted analogues of oxytocin have enhanced O/A selectivity. [8][9][10][11] In most this stems from reduced antidiuretic activity rather than enhanced oxytocic activity. An exception is [Thr4] oxytocin which shows both enhanced oxytocic activity and depressed antidiuretic activity, relative to those of oxytocin.…”

[1-Deaminopenicillamine,4-threonine]oxytocin, a potent inhibitor of oxytocin

“…[4-Threonine]oxytocin is thus a highly potent and specific oxytocic agent. 7,8 The enhanced oxytocic activity could result from (a) increased affinity for the smooth muscle receptors, (b) increased intrinsic activity subsequent to binding, or (c) relative resistance to enzymatic inactivation in the vicinity of the receptors. If the enhanced activity is due to greater binding resulting from the presence of the threonine residue at position 4, then, it was reasoned, the substitution 0022-2623/78/1821-0179$01.00/0 of threonine in an oxytocin antagonist might also increase its binding and consequently give rise to an enhancement of its antagonist properties.…”