ABSTRACT
The clinical treatment of moderate to severe pain relies on traditional opioid analgesics, such as morphine (1) [1a,b] and fentanyl (2) (Fig. 1) [1]. Morphine is one of several known related alkaloids isolated or derived from the opium poppy (Papaver somniferum). The pharmacological properties of opium extracts have been recognized for thousands of years, and their ability to dampen the sensation of pain has been used clinically for centuries. Fentanyl and related 4-substituted piperidine opioids were discovered over the last 75 years and have found great therapeutic utility in pain management [2]. While these two classes of opioid ligands produce profound analgesia, their use is also associatedwith some deleterious physiological effects, such as respiratory depression,muscle rigidity, emesis, constipation, and physical dependence [3]. The clinical need for a potent analgesic lacking these harmful and sometimes fatal additional effects continues today, and the search for ligands that meet
this need has been a research focus for pharmacologists and medicinal chemists for decades.
