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, δ, μ and κ, 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 δ 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 χ 1, y and ω 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 δ 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 μ binding affinity and decrease κ binding affinity, while a positively charged group should increase κ binding and diminish μ binding, although the magnitude of the changes observed is small.