Oxytocin (OT) is an exciting potential therapeutic agent, but it is highly sensitive to modification and suffers extensive degradation at elevated temperature and in vivo. Here we report studies towards OT analogs with favorable selectivity, affinity and potency towards the oxytocin receptor (OTR), in addition to improving stability of the peptide by bridging the disulfide region with substituted dibromo-xylene analogs. We found a sensitive structure-activity relationship in which meta-cyclized analogs (dOT_meta) gave highest affinity (50 nM K_i), selectivity (34-fold), and agonist potency (34 nM EC₅₀, 87-fold selectivity) towards OTR. Surprisingly, ortho-cyclized analogs demonstrated OTR and vasopressin V_1a receptor subtype affinity (220 nM and 69 nM, respectively) and pharmacological activity (294 nM and 35 nM, respectively). V_1a binding and selectivity for ortho-cyclized peptides could be improved 6-fold by substituting a neutral residue at position 8 with a basic amino acid, providing potent antagonists (14 nM IC₅₀) that displayed no activation of the OTR. Furthermore, xylene-bridged analogs demonstrated increased stability compared to OT at elevated temperature, demonstrating promising therapeutic potential for these analogs which warrants further study.

催产素（OT）是一种令人兴奋的潜在治疗剂，但它对修饰高度敏感，并在高温和体内遭受广泛降解。在这里，我们报告了对OT类似物的研究，该研究对催产素受体（OTR）具有良好的选择性，亲和力和效力，此外还通过用取代的二溴二甲苯类似物桥接二硫键区域来提高肽的稳定性。我们发现在其中间环化类似物（DOT敏感结构-活性关系_的元），得到最高的亲和力（50nM的ķ_我），选择性（34倍），和激动剂效力（34 nM的EC ₅₀，87倍的选择性）朝向OTR。出人意料的是，邻环化的类似物证明了OTR和加压素V _1a受体亚型亲和力（分别为220 nM和69 nM）和药理活性（分别为294 nM和35 nM）。通过用碱性氨基酸取代位置8处的中性残基，可以提高对邻环化肽的V _1a结合力和选择性6倍，从而提供不显示OTR活化作用的强效拮抗剂（14 nM IC ₅₀）。此外，在高温下，与OT相比，二甲苯桥接的类似物表现出更高的稳定性，证明了这些类似物的有希望的治疗潜力，值得进一步研究。