Redefining the structure-activity relationships of 26-methano-3-benzazocines. Part 9: Synthesis characterization and molecular modeling of pyridinyl isosteres of N-BPE-8-CAC (1) a high affinity ligand for opioid receptors

摘要

Derivatives of the lead compound N-BPE-8-CAC (>1) where each CH of the biphenyl group was individually replaced by N were prepared in hopes of identifying high affinity ligands with improved aqueous solubility. Compared to >1, binding affinities of the five possible pyridinyl derivatives for the μ opioid receptor were between 3-fold lower to 5-fold higher with the Ki of the most potent compound being 0.064 nM. Docking of 8-CAC (>2) into the unliganded binding site of the mouse μ opioid receptor (pdb: 4DKL) revealed that 8-CAC and β-FNA (from 4DKL) make nearly identical interactions with the receptor. However, for >1 and the new pyridinyl derivatives >4–>8, binding is not tolerated in the 8-CAC binding mode due to the steric constraints of the large N-substituents. Either an alternative binding mode or rearrangement of the protein to accommodate these modifications may account for their high binding affinity.