Probes for Narcotic Receptor Mediated Phenomena. 34. Synthesis and Structure−Activity Relationships of a Potent μ-Agonist δ-Antagonist and an Exceedingly Potent Antinociceptive in the Enantiomeric C9-Substituted 5-(3-Hydroxyphenyl)-N-phenylethylmorphan Series

Abstract

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.

Paradoxical relationship between RAVE (relative activity versus endocytosis) values of several opioid receptor agonists and their liability to cause dependence

“…The mean fluorescence of stained cells minus the mean fluorescence of unstained cells was used to calculate the percentage of surface receptor staining. [20,21] , morphine stimulated binding of [ 35 S]GTPγS to membranes of CHO-HA-MOR cells with an EC 50 value of 15.69±4.76 nmol/L which was approximately 3000-20 000 times greater than that of F9202, F9204, and DHE. Based on the EC 50 values, the rank order of these agonists' ability to activate G protein was DHE>F9204>F9202>morphine.…”

Synthesis and pharmacological effects of the enantiomers of the N-phenethyl analogues of the ortho and para e- and f-oxide-bridged phenylmorphans

“…The oil-coated crystal was mounted on a glass rod and transferred immediately to the cold stream (93 °K) on the diffractometer. The crystal was orthorhombic in space group P2 1 …”

Attention-deficit-hyperactivity disorder and reward deficiency syndrome

“…For example, it has been shown that pharmacological manipulations that increase extracellular serotonin attenuate stimulant effects produced by dopamine release, such as locomotor stimulation and selfadministration behavior. Finally, they discuss their recently published data about PAL-287 (naphthylisopropylamine), a novel non-amphetamine dopamine/serotonin-releasing agent that suppresses cocaine self-administration but lacks positive reinforcing properties (Hiebel et al 2007). Using this concept we have developed the Synaptamine Complex (SG8839) ™ and have recently published on its effects (Chen et al 2004).…”