Modulation of opioid receptor affinity and efficacy via N-substitution of 9β-hydroxy-5-(3-hydroxyphenyl)morphan: Synthesis and computer simulation study.
The enantiomers of a variety of N-alkyl-, N-aralkyl-, and N-cyclopropylalkyl-9β-hydroxy-5-(3-hydroxyphenyl)morphans were synthesized employing cyanogen bromide and K2CO3to improve the original N-demethylation procedure. Their binding affinity to the μ-, δ-, and κ-opioid receptors (ORs) was determined and functional (GTPγ35S) assays were carried out on those with reasonable affinity. The 1R,5R,9S-enantiomers (1R,5R,9S)-(-)-5-(3-hydroxyphenyl)-2-(4-nitrophenethyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-16), (1R,5R,9S)-(-) 2-cinnamyl-5-(3-hydroxyphenyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-20), and (1R,5R,9S)-(-)-5-(3-hydroxyphenyl)-2-(4-(trifluoromethyl)phenethyl)-2-azabicyclo[3.3.1]nonan-9-ol (1R,5R,9S-15), had high affinity for the μ-opioid receptor (e.g., 1R,5R,9S-16: Ki=0.073, 0.74, and 1.99nM, respectively). The 1R,5R,9S-16 and 1R,5R,9S-15 were full, high efficacy μ-agonists (EC50=0.74 and 18.5nM, respectively) and the former was found to be a partial agonist at δ-OR and an antagonist at κ-OR, while the latter was a partial agonist at δ-OR and κ-OR in the GTPγ35S assay. The enantiomer of 1R,5R,9S-16, (+)-1S,5S,9R-16 was unusual, it had good affinity for the μ-OR (Ki=26.5nM) and was an efficacious μ-antagonist (Ke=29.1nM). Molecular dynamics simulations of the μ-OR were carried out with the 1R,5R,9S-16 μ-agonist and the previously synthesized (1R,5R,9S)-(-)-5-(9-hydroxy-5-(3-hydroxyphenyl-2-phenylethyl)-2-azabicyclo[3.3.1]nonane (1R,5R,9S-(-)-NIH 11289) to provide a structural basis for the observed high affinities and efficacies. The critical roles of both the 9β-OH and the p-nitro group are elucidated, with the latter forming direct, persistent hydrogen bonds with residues deep in the binding cavity, and the former interacting with specific residues via highly structured water bridges.
Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 9800 Medical Center Drive, Bethesda, MD 20892-3373, United States.
Phong M
PM
Truong
Center for Molecular Modeling, Office of Intramural Research, Center for Information Technology, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, United States.
Sergio A
SA
Hassan
Center for Molecular Modeling, Office of Intramural Research, Center for Information Technology, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, United States.
Yong-Sok
YS
Lee
Psychobiology Section, Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224, United States.
Theresa A
TA
Kopajtic
Psychobiology Section, Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224, United States.
Jonathan L
JL
Katz
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, United States.
Aaron M
AM
Chadderdon
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, United States.
John R
JR
Traynor
Center for Biomolecular Science and Engineering, Naval Research Laboratory, Washington DC 20375, United States.
Jeffrey R
JR
Deschamps
Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 9800 Medical Center Drive, Bethesda, MD 20892-3373, United States.
Arthur E
AE
Jacobson
Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 9800 Medical Center Drive, Bethesda, MD 20892-3373, United States. Electronic address: kennerr@mail.nih.gov.
Kenner C
KC
Rice
D066241:Carbon-13 Magnetic Resonance Spectroscopy; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D066244:Proton Magnetic Resonance Spectroscopy; D011957:Receptors, Opioid / Q000187:drug effects* / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization
D009019:Morphinans; D011957:Receptors, Opioid
GTP(γ)(35)S functional studies; Molecular dynamics simulations for an atomic-level rationale; Opioid agonists and antagonists; Opioid receptor binding affinity; μ-, δ- and κ-opioid receptors