title: 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 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.
authors: Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
authors: Melissa A
authors: MA
authors: VanAlstine
authors: Mark P
authors: MP
authors: Wentland
authors: Juan
authors: J
authors: Alvarez
authors: Qing
authors: Q
authors: Cao
authors: Dana J
authors: DJ
authors: Cohen
authors: Brian I
authors: BI
authors: Knapp
authors: Jean M
authors: JM
authors: Bidlack
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003521:Cyclopropanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001713:Biphenyl Compounds; D003521:Cyclopropanes; D008024:Ligands; C583672:N-(2-(1,1'-biphenyl)-4-ylethyl)-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-2,6-methano-3-benzazocine-8-carboxamide; D011725:Pyridines; D011957:Receptors, Opioid