Development of Unique Compounds

Medicinal Chemistry Group

Working closely with Severo Salvadori, University of Ferrara, Ferrara, Italy, Gianfranco Balboni, University of Cagliari, Cagliari, Italy, Y. Okada and Yuko Tsuda, Kobe Gakuin University, Kobe, Japan, Yusuke Sasaki and Akihiro Ambo, Sendai, Japan, Tingyou Li, Jilin University, China, Eugenio Vazquez, University of Santiago, Spain, many other outstanding scientists and their many students, postdoctoral fellows and associates for nearly two decades, and Yunden Jinsmaa, University of Iowa, formerly in our Group. During that time we embarked on a boldly comprehensive approach to understand the minimal components of opioid ligands. Beginning from environmental-derived opioids and using proven drug rational drug design for drug discovery program firmly grounded in the principles of medicinal chemistry and computational chemistry, we applied the principles of pharmacology and physiology to pave the way for the development of new or potential candidate drugs.

Our extensive and seminal design of ligands resulted in compounds that acquired new characteristics. The introduction of Dmt (2',6'-dimethyl-L-tyrosine) at the first position of opioid ligands enhanced their properties by several orders of magnitude. The activity elicited by this remarkable amino acid led to the development of a large family of opioidmimetic substances and was responsible for the upsurge and revitalization of interest in this field; Dmt, is recognized as the key component responsible for the alteration and augmentation of activity of a broad range of unique opioid ligands.

Dmt represents a "potent alliance" with opioids in the formulation of δ-opioid antagonists, δ- and µ-opioid agonists, and bifunctional compounds containing agonist and/or antagonist bioactivities for both receptor. Moreover, we addressed the critical issue of the passage of opioids through the blood brain barrier and developed compounds that more effective than morphine with potential translation into human health initiatives: agonists could control both chronic and acute pain derived from physical trauma, surgery, cancer or other disease states, such as shingles, as well as environmental stress (anxiety, depression, allergens). On the other hand, antagonists should reduce substance abuse to opiate drugs, alleviate alcohol dependency, reduce food consumption, modulate impulse-control disorders (Tourette, autism, ADHD) by acting on neural reward pathways involved in craving behaviors.

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