Redefining the structure-activity relationships of 2,6-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.

Abstract 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 threefold lower to fivefold higher with the K i 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.