Management of moderate to severe pain by clinically used opioid analgesics is associated with a plethora of side effects. Despite many efforts have been dedicated to reduce undesirable side effects, moderate progress has been made. In this work, starting from Tramadol, a series of 3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidine-1-carboxamide derivatives were designed and synthesized, and their in vitro and in vivo activities were evaluated. Our campaign afforded selective μ opioid receptor (MOR) ligand 2a (K: 7.3 ± 0.5 nM; K: 849.4 ± 96.6 nM; K: 49.1 ± 6.9 nM) as potent analgesic with ED of 3.1 mg/kg in 55 °C hot plate model. Its antinociception effect was blocked by opioid antagonist naloxone. High binding affinity toward MOR of compound 2a was associated with water bridge, salt bridge, hydrogen bond and hydrophobic interaction with MOR. The high selectivity of compound 2a for MOR over δ opioid receptor (DOR) and κ opioid receptor (KOR) was due to steric hindrance of compound 2a with DOR and KOR. 2a, a compound with novel scaffold, could serve as a lead for the development of novel opioid ligands.