Stefanucci Azzurra, Marinaccio Lorenza, Pieretti Stefano, Mancuso Joseph A, Stine Carrie, Streicher John M, Mollica Adriano
Department of Pharmacy, "G. D'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy.
National Centre for Drug Research and Evaluation, Istituto Superiore di Sanità, 00161 Rome, Italy.
ACS Omega. 2024 Nov 1;9(45):45214-45220. doi: 10.1021/acsomega.4c06449. eCollection 2024 Nov 12.
Biphalin is a bivalent μ/δ opioid receptor agonist showing a promising therapeutic profile with reduced side effects, but as a peptide is limited by poor metabolic stability and blood-brain barrier penetration. To improve these features, we developed the ligand and showed initial in vivo efficacy. To further explore the druggability of this ligand, in this report, we tested metabolic stability in human plasma, receptor engagement by 3 different routes of administration using the tail-flick test, and efficacy in 2 different pathological and chronic pain models. We found that had high stability in plasma and could produce target engagement and a tail flick response. We also showed that had high analgesic efficacy in CIPN but no efficacy in paw incision. Together, these findings suggest that has improved metabolic stability and brain penetration in vivo, prompting further development in clinical testing.
双啡肽是一种二价μ/δ阿片受体激动剂，具有良好的治疗前景且副作用减少，但作为一种肽，它受到代谢稳定性差和血脑屏障穿透性的限制。为改善这些特性，我们开发了该配体并展示了初步的体内疗效。为进一步探索该配体的成药潜力，在本报告中，我们测试了其在人血浆中的代谢稳定性、通过甩尾试验使用3种不同给药途径的受体结合情况以及在2种不同病理和慢性疼痛模型中的疗效。我们发现该配体在血浆中具有高稳定性，能够产生靶点结合和甩尾反应。我们还表明该配体在化疗引起的周围神经病变中具有高镇痛疗效，但在爪部切开模型中无效。总之，这些发现表明该配体在体内具有改善的代谢稳定性和脑穿透性，促使其在临床试验中进一步开发。
