The Drug Design and Synthesis Section of the Chemical Biology Research Branch conducts many activities related to the development of novel compounds with specific biological activities. The Section’s work focuses on three areas. The first involves the synthesis and characterization of opioid ligands with novel therapeutic properties. For example, the Section has developed a number of enantiomers of the oxide-bridged 5-(3-hydroxyphenyl)morphan structure. In particular, the Section has prepared 12 racemates that possess a methyl group, and 12 racemates that possess a 2-phenethyl group. Four of these compounds are quite potent, and the racemic N-phenethyl ortho-c isomer is particularly promising because it should provide a systemically active enantiomer with subnanomolar mu antagonist activity. The Section is currently refining steps in the synthesis process to increase the yield of these compounds. Additionally, the Section has shown that (+) naloxone and (+) naltrexone antagonize the toll-like receptor 4 (TLR4), which is implicated in neuropathic pain, compromised acute opioid analgesia, and addiction. The selective TLR4 antagonist properties of (+) naloxone and (+) naltrexone make them promising therapies, and the Section has shown that (+) naloxone reverses acute and chronic neuropathic pain, prevents cocaine reinforcement, and blunts the acute effects of ethanol.

The Section is also developing enantiomers of unbridged phenylmorphans with mu agonist and delta antagonist properties – a combination that could provide the ideal mixture of strong analgesic effects without the development of tolerance, dependence and reward. The Section’s second area of investigation involves the synthesis and characterization of ligands for corticotropin releasing hormone receptor (CRHR1), which is thought to be involved in most behavioral and physiological responses to stress. The Section is currently trying to synthesize the first CRHR1 ligands for use in PET and SPECT scans, in the hopes of accelerating understandings of the pathophysiology of stress-related diseases. It is also studying the properties of a small molecule CRHR1 ligand that has advanced to Stage III clinical trial, along with another ligand that is easier to synthesize. The third area of investigation focuses on the development of epoxyresibufogenin formate (ERBF) molecules. These molecules are clinically relevant because they antagonize the interleukin-6 (IL-6) receptor, which is implicated in many disorders, including CNS inflammation, osteoporosis, cardiomyopathy, multiple sclerosis, major depression, obesity and diabetes. In particular, the Section has shown that 20R-ERBF is a competitive inhibitor of IL-6, which suppresses cancer cachexia in a mouse model of colon cancer. This compound is orally available and could mark a significant improvement over hormone therapies for IL-6-related disorders, which are prohibitively expensive.