Opioid analgesics are the cornerstone drugs for the treatment of moderate-to-severe pain. Morphine and other analgesics like fentanyl, oxycodone and oxymorphone activate the µ opioid (MOP) receptor, the main type targeted for pharmacotherapy of pain. These drugs share the same pharmacological profiles including severe adverse effects such as respiratory depression, constipation, tolerance and physical dependence. Chemical approaches towards the identification of novel MOP analgesics with reduced side effects include structural modifications of morphinan-6-ones in key positions that are important for binding, selectivity, potency and efficacy at opioid receptors. A representative example is the development of the 14-O-methyl-substituted derivative of the clinically used MOP analgesic oxymorphone, namely 14-O-methyloxymorphone, and its 5-methyl-substituted analogue, 14-methoxymetopon. The focus of the present work is on structure-activity relationship (SAR) studies and in vitro and in vivo pharmacological investigations on a series of opioid ligands differently substituted in positions 5 and 14 of the morphinan skeleton.