Probes for narcotic receptor mediated phenomena. 34. Synthesis and structure-activity relationships of a potent mu-agonist delta-antagonist and an exceedingly potent antinociceptive in the enantiomeric C9-substituted 5-(3-hydroxyphenyl)-N-phenylethylmorphan series.
Both of the enantiomers of 5-(3-hydroxyphenyl)-N-phenylethylmorphan with C9alpha-methyl, C9-methylene, C9-keto, and C9alpha- and C9beta-hydroxy substituents were synthesized and pharmacologically evaluated. Three of the 10 compounds, (1R,5R,9S)-(-)-9-hydroxy-5-(3-hydroxyphenyl-2-phenylethyl-2-azabicyclo[3.3.1]nonane ((1R,5R,9S)-(-)-10), (1R,5S)-(+)-5-(3-hydroxyphenyl)-9-methylene-2-phenethyl-2-azabicyclo[3.3.1]nonane ((1R,5S)-(+)-14), and (1R,5S,9R)-(-)-5-(3-hydroxyphenyl)-9-methyl-2-phenethyl-2-azabicyclo[3.3.1]nonane ((1R,5S,9R)-(+)-15) had subnanomolar affinity at mu-opioid receptors (Ki = 0.19, 0.19, and 0.63 nM, respectively). The (1R,5S)-(+)-14 was found to be a mu-opioid agonist and a mu-, delta-, and kappa-antagonist in [35S]GTP-gamma-S assays and was approximately 50 times more potent than morphine in a number of acute and subchronic pain assays, including thermal and visceral models of nociception. The (1R,5R,9S)-(-)-10 compound with a C9-hydroxy substituent axially oriented to the piperidine ring (C9beta-hydroxy) was a mu-agonist about 500 times more potent than morphine. In the single-dose suppression assay, it was greater than 1000 times more potent than morphine. It is the most potent known phenylmorphan antinociceptive. The molecular structures of these compounds were energy minimized with density functional theory at the B3LYP/6-31G* level and then overlaid onto (1R,5R,9S)-(-)-10 using the heavy atoms in the morphan moiety as a common docking point. Based on modeling, the spatial arrangement of the protonated nitrogen atom and the 9beta-OH substituent in (1R,5R,9S)-(-)-10 may facilitate the alignment of a putative water chain enabling proton transfer to a nearby proton acceptor group in the mu-opioid receptor.
Hiebel
Anne-Cécile
AC
Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse, National Institutes of Health, DHHS, Bethesda, MD 20892, USA.
Lee
Yong Sok
YS
Bilsky
Edward
E
Giuvelis
Denise
D
Deschamps
Jeffrey R
JR
Parrish
Damon A
DA
Aceto
Mario D
MD
May
Everette L
EL
Harris
Louis S
LS
Coop
Andrew
A
Dersch
Christina M
CM
Partilla
John S
JS
Rothman
Richard B
RB
Cheng
Kejun
K
Jacobson
Arthur E
AE
Rice
Kenner C
KC
D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D000882:Haplorhini; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011789:Quantum Theory; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C524100:9-hydroxy-5-(3-hydroxyphenyl)-2-phenylethyl-2-azabicyclo(3.3.1)nonane; D000700:Analgesics; D019086:Bridged Bicyclo Compounds, Heterocyclic; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu