Since PA-8 (5-(4-(Allyloxy)-3-methoxyphenyl)-2-amino-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione) was recently identified as a novel small-molecule antagonist of the pituitary adenylate cyclase-activating polypeptide (PACAP) type I (PAC1) receptor, a series of pyrido[2,3-d]pyrimidine derivatives have been designed, synthesized and subsequently evaluated for antagonistic activity on the PAC1 receptor. In this study, we synthesized 21 derivatives based on the PA-8 structure. Among them, the compound 2o (2-Amino-5-(3-trifluoromethoxy-phenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione) showed more potent antagonistic activities than PA-8. Intrathecal (i.t.) injection of 2o blocked the induction of PACAP-induced aversive behaviors and mechanical allodynia in mice, and the effects were more potent than those of PA-8. A single i.t. injection of 2o also inhibited spinal nerve ligation (SNL)-induced mechanical allodynia. Repeated intraperitoneal administration of 2o gradually reduced the SNL-induced mechanical allodynia, and this effect appeared earlier than for PA-8. In addition, 2o exhibited a favorable ADME and pharmacokinetics profiles. These results suggest that 2o may become an analgesic for the treatment of neuropathic pain.

由于 PA-8 (5-(4-(Allyloxy)-3-methoxyphenyl)-2-amino-5,8-dihydro-3 H ,6 H - pyrido[2,3 - d ]pyrimidine-4,7-dione ) 最近被确定为一种新型的垂体腺苷酸环化酶激活多肽 (PACAP) I 型 (PAC1) 受体小分子拮抗剂，一系列吡啶并[2,3- d ]嘧啶衍生物已被设计、合成并随后进行了评估对 PAC1 受体有拮抗作用。在这项研究中，我们合成了 21 种基于 PA-8 结构的衍生物。其中，化合物2o (2-氨基-5-(3-三氟甲氧基-苯基)-5,8-二氢-3H,6H-吡啶并[ 2,3 - d]pyrimidine-4,7-dione) 显示出比 PA-8 更有效的拮抗活性。鞘内（it）注射2o阻断了 PACAP 诱导的小鼠厌恶行为和机械异常性疼痛的诱导，并且效果比 PA-8 更有效。单次注射2o也可抑制脊神经结扎 (SNL) 引起的机械性异常性疼痛。2o的重复腹腔内给药逐渐减少了 SNL 引起的机械异常性疼痛，并且这种效果比 PA-8 更早出现。此外，2o表现出良好的 ADME 和药代动力学特征。这些结果表明，2o可能成为治疗神经性疼痛的镇痛剂。