Development of novel LP1-based analogues with enhanced delta opioid receptor profile

Pain relief achieved by co-administration of drugs acting at different targets is more effective than that obtained with conventional MOR selective agonists usually associated to relevant side effects. It has been demonstrated that simultaneously targeting different opioid receptors is a more effective therapeutic strategy. Giving the promising role for DOR in pain management, novel LP1-based analogues with different N-substituents were designed and synthesized with the aim to improve DOR profile. For this purpose, we maintained the phenyl ring in the N-substituent of 6,7-benzomorphan scaffold linked to an ethyl spacer bearing a hydroxyl/methyl or methoxyl group at carbon 2 or including it in a 1,4-benzodioxane ring. LP1 analogues were tested by competition binding assays. Compounds 6 (K-i(MOR) = 2.47 nM, K-i(DOR) = 9.6 nM), 7 (K-i(DOR) = 0.5 nM and K-i(DOR) = 0.8 nM) and 9 (K-i(DOR) = 1.08 nM, K-i(DOR) = 6.6 nM) retained MOR affinity but displayed an improved DOR binding capacity as compared to LP1 (K-i(DOR) = 0.83 nM