Structural Modification and Development of N-(1,2,3,4-Tetrahydro-3-isoquinolinylmethyl)benzamide, BPR1M492, as a Potent and Rapid-Onset Opioid Analgesic with Reduced Withdrawal Symptoms.

A series of N-(1,2,3,4-tetrahydro-3-isoquinolinylmethyl)benzamides, which are potent μ-opioid receptor (MOR) agonists, has been discovered. The most promising compound, compound 56 (BPR1M492), is an MOR agonist without a clear signaling bias between cAMP and β-arrestin-2 pathways, a cAMP-biased nociceptin-orphanin FQ opioid peptide agonist, and a weak cAMP-biased δ/κ-opioid receptor agonist. Compound 56 demonstrated potent in vivo antinociception at 0.027 mg/kg, offering rapid pain relief within 5 min of subcutaneous injection. It produced markedly milder withdrawal symptoms than TRV130 in mice, whereas differences in respiratory, gastrointestinal, reward-related, and tolerance-related measures were less pronounced and should be interpreted cautiously in light of the substantially lower dose required for antinociception. Compound 56 is a highly stable, slightly hygroscopic, low-moisture-containing crystalline solid that is safe at its in vivo effective dose.