Despite the extensive research to provide a disease-modifying osteoarthritis drug (DMOAD), there is still no approved DMOAD. Dual amylin and calcitonin receptor agonists (DACRA) can provide metabolic benefits along with antinociceptive and potential structural preserving effects. In these studies, we tested a DACRA named KBP-336 on a metabolic model of OA in meniscectomised (MNX) rats. We evaluated KBP-336’s effect on pain-like symptoms in Sprague Dawley (SD) rats on high-fat diet (HFD) that underwent meniscectomy using the von Frey test to measure the 50% paw withdrawal threshold (PWT) and analyzed using one-way ANOVA. Short in vivo studies and in vitro cell receptor expression systems were used to illustrate receptor pharmacology. After 30 weeks on HFD, including an 8-week treatment, female MNX animals receiving KBP-336 4.5 nmol/Kg/72 h had lower body weight and smaller adipose tissues than their vehicle-treated counterparts. After 20 weeks on HFD, including an 8-week treatment, male rats receiving KBP-336 had lower body weight than the vehicle group. In both the female and male rats, the MNX groups on KBP-336 treatment had a higher PWT than the vehicle-treated MNX group. Aiming to identify the receptor influencing pain alleviation, KBP-336 was compared to the long-acting human calcitonin (hCTA). Single-dose studies on 12-week-old male rats showed that hCTA lowers CTX-I without affecting food intake, confirming its calcitonin receptor selectivity. On the metabolic OA model with 18 weeks of HFD, including 6-week treatment, hCTA at 100 nmol/Kg/24 h and KBP-336 at 0.5, 1.5, and 4.5 nmol/Kg/72 h produced significantly higher PWT in MNX animals compared to MNX animals on vehicle treatment. hCTA and KBP-336 at 0.5 nmol/Kg did not affect body weight and fat tissues. Overall, KBP-336 improved the pain observed in the metabolic OA model. Calcitonin receptor activation proved to be essential in this antinociceptive effect.

中文翻译：

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胰淀素和降钙素受体双重激动剂 KBP-336 具有减肥、镇痛和骨骼保护的独特组合——一种新型缓解骨关节炎疾病的药物


尽管针对改善骨关节炎疾病药物 (DMOAD) 进行了广泛的研究，但仍然没有获得批准的 DMOAD。双胰淀素和降钙素受体激动剂 (DACRA) 可以提供代谢益处以及抗伤害和潜在的结构保护作用。在这些研究中，我们在半月板切除 (MNX) 大鼠的 OA 代谢模型上测试了名为 KBP-336 的 DACRA。我们评估了 KBP-336 对接受高脂饮食 (HFD) 的 Sprague Dawley (SD) 大鼠的疼痛样症状的影响，这些大鼠接受半月板切除术，使用 von Frey 试验测量 50% 缩爪阈值 (PWT)，并使用一-方式方差分析。使用简短的体内研究和体外细胞受体表达系统来说明受体药理学。经过 30 周的 HFD 治疗（包括 8 周的治疗）后，接受 KBP-336 4.5 nmol/Kg/72 小时的雌性 MNX 动物与媒介物治疗的动物相比，体重更低，脂肪组织更小。经过 20 周的 HFD 治疗（包括 8 周的治疗）后，接受 KBP-336 的雄性大鼠的体重低于媒介物组。在雌性和雄性大鼠中，接受 KBP-336 治疗的 MNX 组的 PWT 高于接受媒介物治疗的 MNX 组。为了确定影响疼痛缓解的受体，将 KBP-336 与长效人降钙素 (hCTA) 进行了比较。对 12 周龄雄性大鼠的单剂量研究表明，hCTA 降低 CTX-I 而不影响食物摄入，证实了其降钙素受体选择性。在 HFD 18 周（包括 6 周治疗）的代谢 OA 模型中，100 nmol/Kg/24 小时的 hCTA 和 0.5、1.5 和 4.5 nmol/Kg/72 小时的 KBP-336 在 MNX 动物中产生显着更高的 PWT与接受载体治疗的 MNX 动物相比。 0.5 nmol/Kg 的 hCTA 和 KBP-336 不影响体重和脂肪组织。 总体而言，KBP-336 改善了代谢性 OA 模型中观察到的疼痛。事实证明，降钙素受体激活对于这种抗伤害作用至关重要。