Adachi Yusuke, Sakimura Katsuya, Shimizu Yuji, Nakayama Masaharu, Terao Yasuko, Yano Takahiko, Asami Taiji
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa 251-8555, Japan.
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa 251-8555, Japan.
Bioorg Med Chem Lett. 2017 Jun 1;27(11):2331-2335. doi: 10.1016/j.bmcl.2017.04.030. Epub 2017 Apr 12.
Oxytocin (OT) is a neuropeptide involved in a wide variety of physiological actions, both peripherally and centrally. Many human studies have revealed the potential of OT to treat autism spectrum disorders and schizophrenia. OT interacts with the OT receptor (OTR) as well as vasopressin 1a and 1b receptors (VR, VR) as an agonist, and agonistic activity for VR and VR may have a negative impact on the therapeutic effects of OTR agonism in the CNS. An OTR-selective agonistic peptide, FE 202767, in which the structural differences from OT are a sulfide bond instead of a disulfide bond, and N-alkylglycine replacement for Pro at position 7, was reported. However, the effects of amino acid substitutions in OT have not been comprehensively investigated to compare OTR, VR, and VR activities. This led us to obtain a new OTR-selective analog by comprehensive amino acid substitutions of OT and replacement of the disulfide bond. A systematic amino acid scanning (Ala, Leu, Phe, Ser, Glu, or Arg) of desamino OT (dOT) at positions 2, 3, 4, 5, 7, and 8 revealed the tolerability for the substitution at positions 7 and 8. Further detailed study showed that trans-4-hydroxyproline (trans-Hyp) at position 7 and γ-methylleucine [Leu(Me)] at position 8 were markedly effective for improving receptor selectivity without decreasing the potency at the OTR. Subsequently, a combination of these amino acid substitutions with the replacement of the disulfide bond of dOT analogs with a sulfide bond (carba analog) or an amide bond (lactam analog) yielded several promising analogs, including carba-1-[trans-Hyp,Leu(Me)]dOT (14) with a higher potency (7.2pM) at OTR than that of OT and marked selectivity (>10,000-fold) over VR and VR. Hence, we investigated comprehensive modification of OT and obtained new OT analogs that exhibited high potency at OTR with marked selectivity. These OTR-selective agonists could be useful to investigate OTR-mediated effects on psychiatric disorders.
催产素（OT）是一种神经肽，在周围和中枢参与多种生理活动。许多人体研究揭示了OT治疗自闭症谱系障碍和精神分裂症的潜力。OT作为激动剂与OT受体（OTR）以及血管加压素1a和1b受体（VR1、VR2）相互作用，而对VR1和VR2的激动活性可能会对OTR激动作用在中枢神经系统中的治疗效果产生负面影响。据报道，有一种OTR选择性激动肽FE 202767，它与OT的结构差异在于用硫醚键取代了二硫键，并且在第7位用N-烷基甘氨酸取代了脯氨酸。然而，尚未对OT中的氨基酸取代效应进行全面研究以比较OTR、VR1和VR2的活性。这促使我们通过对OT进行全面的氨基酸取代并替换二硫键来获得一种新的OTR选择性类似物。对去氨基OT（dOT）的第2、3、4、5、7和8位进行系统的氨基酸扫描（丙氨酸、亮氨酸、苯丙氨酸、丝氨酸、谷氨酸或精氨酸），揭示了第7位和第8位取代的耐受性。进一步的详细研究表明，第7位的反式-4-羟基脯氨酸（trans-Hyp）和第8位的γ-甲基亮氨酸[Leu(Me)]在不降低对OTR的效力的情况下，对提高受体选择性具有显著效果。随后，将这些氨基酸取代与用硫醚键（碳环类似物）或酰胺键（内酰胺类似物）取代dOT类似物的二硫键相结合，产生了几种有前景的类似物，包括碳环-1-[trans-Hyp,Leu(Me)]dOT（14），其对OTR的效力（7.2pM）高于OT，并且对VR1和VR2具有显著的选择性（>10000倍）。因此，我们研究了OT的全面修饰并获得了在OTR上具有高效力和显著选择性的新OT类似物。这些OTR选择性激动剂可能有助于研究OTR介导的对精神疾病的影响。
