SAR studies on a weak delta opioid dipeptide antagonist (Tyr-Tic) and a potent mu opioid peptidomimetic agonist.

The existence of three types of opioid receptors, delta, mu and kappa, as well as their analgesic effects, and associated side effects are well known. Although thousands of opioid peptides and non-peptides have been synthesized, an understanding of the individual pharmacological activity of each receptor type, and the development of analgesics with no adverse side effects are still great challenges. A detailed knowledge of opioid receptor structure and the interaction of opioids at the receptor-binding site are keys for meeting these challenges. This thesis describes structure activity relationship (SAR) studies on two potentially valuable classes of small opioid ligands, Tyr-Tic and BTTQ (6-benzyl-4-tyrosyl-1,2,3,4-tetrahydroquinoline) and relates the observed results to our evolving opioid receptor models. In the Tyr-Tic series, extensive structural modifications performed on the Ti(c) (1,2,3,4-tetrahydroisoquinoline-(3-carboxylic acid)) benzene ring lead to generally decreased delta binding affinities, although lipophilic substituents such as Cl, F and Me are better tolerated. Modifications on various other positions fail to produce promising binding results. Conformational analysis of Tyr-Ti(c) using a grid scan search method with dihedral angles chi 1, y and o as variables identified low energy conformers, which were grouped into conformational families. Comparison with the structurally rigid opiate naltrindole and docking to our receptor model identifies the delta bound conformation of Tyr-Ti(c) as containing trans and gauche (+) orientations of Tyr1 and Tic2 side chains, respectively, a y angle of Tyr1 ∼ 130° and a cis peptide bond. Interactions of ligands with opioid receptor binding sites were also examined. The results are in general agreement with the observed SAR data. BTTQ was designed based on a pharmacophore model derived from the cyclic tetrapeptide peptide cyclo[Tyr-D-Cys-Phe-D-Pen] (JOM-13) with the entire cyclic portion of the peptide replaced by the tetrahydroquinoline scaffold. Various substituents were incorporated at the N1 position through a rationally designed synthetic pathway. The binding data are consistent with the modeling results that predict that a negatively charged group should improve mu binding affinity and decrease kappa binding affinity, while a positively charged group should increase kappa binding and diminish mu binding, although the magnitude of the changes observed is small.PhDOrganic chemistryPure SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/132627/2/9977208.pd