Some pharmacological properties of cyclic and linear analogs obtained by substituting each residue of an oxytocin antagonist with d‐tryptophan

We synthesized 10 analogs (1–10) derived from the sequence of [Pmp¹, D‐Trp², Arg⁸]oxytocin, (parent antagonist or PA), (Pmp =β,β‐pentamethylene‐β‐mercaptopropionic acid) which is a potent antagonist (pA₂= 7.77) of the uterotonic effect of oxytocin (OT) in rats, as determined in our uterotonic assay. Eight of the following analogs were designed by replacement of each residue in the PA sequence, other than the residue at position 2, with d‐tryptophan: Ac‐d‐Trp‐d‐Trp‐Ile‐Gln‐Asn‐Val‐Pro‐Arg‐Gly‐NH₂, (1); [Pmp¹, d‐Trp(For)², Arg⁸] OT, (2); [Pmp¹, d‐Trp², d‐Trp³, Arg⁸] OT, (3); [Pmp¹, D‐Trp², d‐Trp⁴, Arg⁸] OT, (4); [Pmp¹, d‐Trp², d‐Trp⁵, Arg⁸] OT, (5); Aaa‐d‐Trp‐Ile‐Gln‐Asn‐d‐Trp‐Pro‐Arg‐Gly‐NH₂, (6); [Pmp¹, d‐Trp², d‐Trp⁷, Arg⁸] OT, (7); [Pmp¹, d‐Trp², d‐Trp⁸] OT, (8); [Pmp¹, d‐Trp², Arg⁸, d‐Trp⁹] OT, (9); [Pmp¹d‐Trp², Arg⁸, d‐Trp(For)⁹] OT, (10). To avoid free mercaptan groups, Val⁶ was chosen in analog 1 instead of Cys and Aaa¹ (Aaa = 1‐adamantaneacetic acid) in analog 6 instead of Pmp¹. Of the linear analogs, 1 was inactive as an OT antagonist and 6 was a very poor antagonist, with a pA₂= 5.66, but it was more potent than Aaa‐d‐Trp‐Ile‐Gln‐Asn‐Val‐Pro‐Arg‐Gly‐NH₂, which has a pA₂= 5.33, as we had previously reported. Analog 2, featuring d‐Trp(For)², pA₂= 7.37, was weaker than PA, indicating that the formyl group lowers potency. Analogs 3 and 4 were much weaker than PA, and analog 5 was inactive. Hence, other than at position 2, d‐Trp is undesirable in the ring sequence of PA. However, analogs featuring d‐substituents in the tail portion of PA were good antagonists. Replacement with d‐Trp⁷ gave antagonist 7, pA₂= 7.92, which is somewhat more potent than PA. Replacement with d‐Trp⁹ gave antagonist 9, pA₂= 8.18, which is about 2.5 times more potent than PA, although d‐Trp(For)⁹, introduced in analog 10, pA₂= 8.10, was not as potent. Replacement with d‐Trp⁸ results in analog 8, pA₂= 7.83, equipotent with PA. In the antidiuretic assay analogs 7, 8, and 9, each with a pA₂ equal to or less than < 5.6, were very weak antagonists of the antidiuretic hormone, arginine vasopressin (AVP). Hence, the potent analogs 7, 9, and especially 8 which, unlike AVP or the usual OT antagonists, lacks a basic amino acid, are important leads for future design of highly potent and probably, more selective OT antagonists.