Design, Synthesis, and Evaluation of Novel, Multifunctional Dimethyltyrosine-Tetrahydroisoquinoline Opioid Peptidomimetics

Abstract

The opioid receptors modulate a wide variety of physiological and behavioral functions, including pain, mood, and reward. There are three main types of opioid receptors – kappa (KOR), mu (MOR), and delta (DOR), and many agonists and antagonists for these receptors have been developed. Because of the complex pharmacology of this system, selective opioid ligands have limited therapeutic potential; however, multifunctional opioid compounds, those which act simultaneously at more than one type of receptor, have shown clinical promise. It has been well-demonstrated that minor changes in the chemical structure of an opioid ligand can result in drastic changes in the associated pharmacological profile. Therefore, selective opioid scaffolds represent a rational starting point for the development of multifunctional opioid ligands. The dimethyltyrosine-tetrahydroisoquinoline (Dmt-Tiq) scaffold is well-known in the creation of DOR antagonist selective peptides, and many such compounds have been reported. However, the constraints of traditional peptide synthesis have limited the exploration of chemical space surrounding the tetrahydroisoquinoline (Tiq) core. This work reports the repurposing of this classically DOR selective scaffold in the creation of novel, multifunctional opioid peptidomimetics through the introduction of previously unexplored modifications. Installation of a 7-benzyl pendant on the Tiq aromatic ring introduced KOR agonism. Further exploration of the structure-activity relationships surrounding this pendant resulted in the development of compounds which exhibit a variety of multifunctional profiles. Ortho and meta substitution on the 7-benzyl pendant or replacement of the benzyl ring with a bicyclic ring that mimics 1-naphthyl resulted in a KOR agonism and MOR partial agonism. This profile is being explored in the development of a treatment for cocaine addiction, for which there is currently no available therapeutic. Other modifications, including a tetrahydroisoquinoline or isoindoline pendant at the 7-position or replacement of the pendant linker with an aniline, led to a MOR agonist/DOR antagonist profile, which has potential for use as a treatment for pain with lower addiction potential than conventional opioids. Ultimately, the work presented here describes a library of novel Dmt-Tiq opioid peptidomimetics which display a variety of pharmacologically useful multifunctional profiles.