Development of Macrocyclic Neurotensin Receptor Type 2 (NTS2) Opioid‐Free Analgesics

The opioid crisis has highlighted the urgent need to develop non‐opioid alternatives for managing pain, with an effective, safe, and non‐addictive pharmacotherapeutic profile. Using an extensive structure–activity relationship approach, here we have identified a new series of highly selective neurotensin receptor type 2 (NTS2) macrocyclic compounds that exert potent, opioid‐independent analgesia in various experimental pain models. To our knowledge, the constrained macrocycle in which the Ile 12 residue of NT(7–12) was substituted by cyclopentylalanine, Pro 7 and Pro 10 were replaced by allyl‐glycine followed by side‐chain to side‐chain cyclization is the most selective analog targeting NTS2 identified to date ( K i 2.9 nM), showing 30,000‐fold selectivity over NTS1. Of particular importance, this macrocyclic analog is also able to potentiate the analgesic effects of morphine in a dose‐ and time‐dependent manner. Exerting complementary analgesic actions via distinct mechanisms of nociceptive transmission, NTS2‐selective macrocycles can therefore be exploited as opioid‐free analgesics or as opioid‐sparing therapeutics, offering superior pain relief with reduced adverse effects to pain patients.