Department of Pharmaceutical Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
Bioorg Med Chem. 2010 Jul 15;18(14):4975-82. doi: 10.1016/j.bmc.2010.06.005. Epub 2010 Jun 9.
6,7-benzomorphan derivatives, exhibiting different mu, delta, and kappa receptor selectivity profiles depending on the N-substituent, represent a useful skeleton for the synthesis of new and better analgesic agents. In this work, an aromatic ring and/or alkyl residues have been used with an N-propanamide or N-acetamide spacer for the synthesis of a new series of 5,9-dimethyl-2'-hydroxy-6,7-benzomorphan derivatives (12-22). Data obtained by competition binding assays showed that the mu opioid receptor seems to prefer an interaction with the 6,7-benzomorphan ligands having an N-substituent with a propanamide spacer and less hindered amide. Highly stringent features are required for delta receptor interaction, while an N-acetamide spacer and/or bulkier amide could preferentially lead to kappa receptor selectivity. In the propanamide series, compound 12 (named LP1) displayed high mu affinity (Ki=0.83 nM), good delta affinity (Ki=29 nM) and low affinity for the kappa receptor (Ki=110 nM), with a selectivity ratio delta/mu and kappa/mu of 35.1 and 132.5, respectively. Further, in the adenylyl cyclase assay, LP1 displayed a mu/delta agonist profile, with IC50 values of 4.8 and 12 nM at the mu and delta receptors, respectively. The antinociceptive potency of LP1 in the tail-flick test after sc administration in rat was comparable with the potency of morphine (ED50=2.03 and 2.7 mg/kg, respectively), and was totally reversed by naloxone. LP1, possessing a mu/delta agonist profile, could represent a lead in further developing benzomorphan-based ligands with potent in vivo analgesic activity and a reduced tendency to induce side effects.
6,7-苯并吗啡烷衍生物，根据 N-取代基的不同，表现出不同的 μ、δ 和 κ 受体选择性，是合成新型和更好的镇痛剂的有用骨架。在这项工作中，使用芳香环和/或烷基残基以及 N-丙酰胺或 N-乙酰胺间隔物，合成了一系列新的 5,9-二甲基-2'-羟基-6,7-苯并吗啡烷衍生物（12-22）。竞争结合测定的数据表明，μ 阿片受体似乎更喜欢与具有丙酰胺间隔物和较少阻碍酰胺的 N-取代基的 6,7-苯并吗啡烷配体相互作用。对于 δ 受体相互作用，需要高度严格的特征，而 N-乙酰胺间隔物和/或更大的酰胺可能优先导致 κ 受体选择性。在丙酰胺系列中，化合物 12（命名为 LP1）表现出高 μ 亲和力（Ki=0.83 nM）、良好的 δ 亲和力（Ki=29 nM）和对 κ 受体的低亲和力（Ki=110 nM），其 δ/μ 和 κ/μ 的选择性比值分别为 35.1 和 132.5。此外，在腺苷酸环化酶测定中，LP1 表现出 μ/δ 激动剂特性，在 μ 和 δ 受体上的 IC50 值分别为 4.8 和 12 nM。LP1 在 sc 给予大鼠后的尾部闪烁试验中的镇痛效力与吗啡相当（ED50 值分别为 2.03 和 2.7 mg/kg），并被纳洛酮完全逆转。LP1 具有 μ/δ 激动剂特性，可能是进一步开发基于苯并吗啡烷的具有强大体内镇痛活性和降低诱导副作用倾向的配体的先导化合物。
