Probes for Narcotic Receptor Mediated Phenomena. 34. Synthesis and Structure-Activity Relationships of a Potent -Agonist 
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- 作者：Anne-Cé ; cile Hiebel ; Yong Sok Lee ; Edward Bilsky ; Denise Giuvelis ; Jeffrey R. Deschamps ; Damon A. Parrish ; Mario D. Aceto ; Everette L. May ; Louis S. Harris ; Andrew Coop ; Christina M. Dersch ; Joh
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：August 9, 2007
- 年：2007
- 卷：50
- 期：16
- 页码：3765 - 3776
- 全文大小：299K
- 年卷期：v.50,no.16(August 9, 2007)
- ISSN：1520-4804
文摘
Both of the enantiomers of 5-(3-hydroxyphenyl)-N-phenylethylmorphan with C9
-methyl, C9-methylene,C9-keto, and C9- and C9
-hydroxy substituents were synthesized and pharmacologically evaluated. Threeof 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 
-opioid receptors (Ki = 0.19, 0.19, and0.63 nM, respectively). The (1R,5S)-(+)-14 was found to be a -opioid agonist and a -, 
-, and 
-antagonistin [35S]GTP-
-S assays and was approximately 50 times more potent than morphine in a number of acuteand subchronic pain assays, including thermal and visceral models of nociception. The (1R,5R,9S)-(-)-10compound with a C9-hydroxy substituent axially oriented to the piperidine ring (C9-hydroxy) was a -agonistabout 500 times more potent than morphine. In the single-dose suppression assay, it was greater than 1000times more potent than morphine. It is the most potent known phenylmorphan antinociceptive. The molecularstructures 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 commondocking point. Based on modeling, the spatial arrangement of the protonated nitrogen atom and the 9-OHsubstituent in (1R,5R,9S)-(-)-10 may facilitate the alignment of a putative water chain enabling protontransfer to a nearby proton acceptor group in the -opioid receptor.
-methyl, C9-methylene,C9-keto, and C9- and C9-hydroxy substituents were synthesized and pharmacologically evaluated. Threeof 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 -opioid receptors (Ki = 0.19, 0.19, and0.63 nM, respectively). The (1R,5S)-(+)-14 was found to be a -opioid agonist and a -, -, and -antagonistin [35S]GTP--S assays and was approximately 50 times more potent than morphine in a number of acuteand subchronic pain assays, including thermal and visceral models of nociception. The (1R,5R,9S)-(-)-10compound with a C9-hydroxy substituent axially oriented to the piperidine ring (C9-hydroxy) was a -agonistabout 500 times more potent than morphine. In the single-dose suppression assay, it was greater than 1000times more potent than morphine. It is the most potent known phenylmorphan antinociceptive. The molecularstructures 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 commondocking point. Based on modeling, the spatial arrangement of the protonated nitrogen atom and the 9-OHsubstituent in (1R,5R,9S)-(-)-10 may facilitate the alignment of a putative water chain enabling protontransfer to a nearby proton acceptor group in the -opioid receptor.